### UNITED STATES ENVIRONMENTAL PROTECTION AGENCY

WASHINGTON , D

. C

. 2 04 6 0

OFFICE OF CHE MI CAL SAFETY AND POLL U TIO N PREVE N TIO N



### MEM OR AN D UM

Date: I 0 May 2016

SUBJECT: Fluensulfone

- Aggregate Human Health Risk Assessment Addressing Lab e l A mendment s, Changes to the Residue Definition

, and New Uses on Multiple Crops

.

FROM: P C Code: 0504 I 0

Decision Nos.: 50 I 793, 507767, 508627, 509477 DP Barcodes: D427486

, D428909

, D429293, D42980 I Registration Nos.: 66222-243

, 66222- EAE

, 53883-GL T
Petition Nos.: 5F835 I
, 5E8384 Regulatory Actions: Section 3 Registration and Label Amendments
Ri s k Assessment Type: Single Chemica l Aggrega te Case No.: NA

TXR No.: NA CAS No.: 3 I 8290 -98- I
MRJD No.: See Attachment I 40 CFR: I 80.680



### Michael A. 

### Doherty, Ph.D.

, Se nior

# Chemi~t . 

# t{]J / 

# JJanet Cowins, Ph .D., Chemist •

# ~ Jaime D ' Agostino, Ph.D., To xico logist

### .._~**~** Zaida Figueroa

, DrPH

.. Indu st r ial H ygienist Gerad Thornton, Environmental Protection Specialist Ri sk Assessment Branch II Health Effects Division (7509P)

THROUGH: Chr istina Swartz

, C hi ef 

### I} 

# n ' /\ ,.-- Risk Assessme nt Branch II

### ~**~** Health Effects Divi s ion (7509P)



### TO: Rita Kumar/Mark Suare z/ Meredith Laws In vertebrate and Vertebrate Branch 3 R eg i st ration Divi sio n (7505P)

A ndr ew E rtman/Barbara Madden/Marion John so n Risk Int egra ti on, M in or Use, and Emergency Response Branch Registration Division (7505P)

Page 1 of 57

### Fluensulfone D427486

1.0 Executive Summary

.............................................................. . .............................................. 4 2.0 HED Recommendation s

..... . ......... .. ........ . ............................. . ............................................... 6 2. l Data Deficiencies

............................................................................................................. 6 2.2 To l erance Conside r ations

. ........ .. ........ .. ............................................................................ 6 2.2. 1 Enforcem ent Analytical Method

..... ... ........ ................................................ ............... 7 2.2.2 R ecommended Tolerance s

.. ........ .. .... . ............................................... . ........ . ........ . . . ... 7 2.2.3 Re vis ion s to Petitioned-For Tolerances

........................... ............... .......................... 7 2.2.4 International Harmoni za tion

....................................... . .......... . ...... . .. . ............. .... . ...... 8 2.3 Label R eco mmendati ons

................................................... . .......... . ...... . .. . ................. . ....... 9 2 .3

. 1 Recomm e ndation s from Residue R ev iew s

............................................................... 9 2.3.2 Recommendation s from Occupationa l Assessment..

................................................ 9 2.3.3 Rec o mmendation s from Residential Assessment

. ..... . ............................................ I 0 3.0 Introduction

.. . ..... .. .................... ............... ................................ . .......... . ...... . .. . ..... . .. . .. . .... . .. . . 10 3.1 Chemical Identi ty

......................................... .. ................................................................ 10 3.2 P h ysica l /C hemica l Character i stics

.... .. ......... . ........ . ........................................................ 11 3.3 Pesticide Use Pattern

...................................................................................................... 11 3 .4 Anticipated Exposure Pathways

....... . ... . ..... . ............. . ....... . ........... . ......... . ...................... 14 3.5 Consideration of Environmental Ju s tice

.......................... . .......... . .......... . ........ . .......... . ... 14 4.0 Hazard Characterizat i on and Do se -R espo n se Assessment

................................................ 15 4.1 Summary of Toxicological Effec t s

................................................................................ 15 4.2 Absorption, D i s tribution

, Metabolism, & El imination (A DM E)

.. ................................. 16 4.2. 1 Derma l Absorption

.. .. ........ .. ........ .. ......... . ......... . ....... .. ......... .. ...... . . .. .. . ........ . . . ..... . .. . . 16 4.3 Toxicological Effects

..................................................................................................... 17 4.4 Safety Factor for Infants and Children (FQPA Safety Factor)

............ . ........ . ........ . . .. .... 19 4.4.1 Completeness of the To xi col ogy Database

.. ... ....... . ......... ...... ............ ..................... 19 4.4

. 2 Evide n ce of Neurotoxicity

................... . .................. . .......... . ......... . .. .. ....... . ........ . .. . .. 20 4.4.3 Evidence of Sensitivity / Susceptibility in the Developin g or Young Animal

..... . . . . 20 4.4.4 Re s idual U ncertainty in the Exposure Database

........ . .......... . ................................. 20 4.5 Toxicity E ndpoint and Point of Departure Select i on s

..... . .......... . ......... . .... .. ... . .............. 2 0 4.5

. l Do se- Re s ponse Assess ment

...... ......... . ............... ... .......................... . ........ . ...... .. ...... 20 4.5.2 Rec o mmendation for Combining Routes of Exposures for Ri s k Assessment..

. ..... 23 4.5.3 Cancer C la ss ification and Risk Assessment Recommendation

.............................. 24 4.5.4 Summary of Points of Departu r e and Toxic i ty Endpo i nt s Use d in Human Risk Assessme nt

....................................................................................................................... . .... 24 5.0 D i eta r y Exposure and R i sk Assessment..

............... . ... . ....... .. .. . ....... .. ........ .. .. . ............. ........ 26 5.1 Residues of Concern Summary and Rati ona l e

..................................... . .... . ............... . .... 26 5.2 Food Re s idu e Profil e

.................................... . ........ .. ........ . .. . ....... . .... ...... ........................ . 27 5.3 Water R es idu e Profile

.. . ...... ... .. ......... . ............................................ .. ........................ . ..... 27 5 .4 Di e tary Risk Assessment

....... .. ......... .. ........ .. ................................... .... ..... .... ................. 28 5.4.1 De scrip tion of R es idue Data Use d in Dietary Assessment..

........ . ... . ....... . .......... . ... 28 5.4.2 Perc e nt Crop Treated Used in Dietary Assessment

...... ..... ......... .. ...... .................... 28 5.4.3 Acute and Chronic Dietary Risk Assessment

.................... .. ......... . .. . ........ . ............. 28 6.0 

### 6. l 6.2 6.3 Residential (Non -Occupation al) Exposu re/Ri sk Characte rizati on

..... ..... ................. . ......... 29 Residential Hand l er Ex posu r e

......... .. ........ .. ... . .... .. ... .. ....... . .. . ................................... . . . ... 29 P ost -Application Exposure

......................................................... . ......... . ..... .... ............... 29 Residential Risk Estimates for Use in Aggregate Assessment

............. . ......... . .............. 30

Page 2 of 57

### Fluensulfone D427486

Page 3 of 57 7.0 Non

- Occupational Bystander Post

- Application Inhalation Exposure and Risk Estimates 31 8.0 Non

- Occupational Spray Drift Exposure and Risk Estimates

................................ ............ 31 9.0 Aggregate Exposure/Risk Characterization

................................ ................................ ....... 32 9.1 Acute Aggregate Risk

................................ ................................ ................................ .... 32 9.2 Short

- Term Aggregate Risk

................................ ................................ ........................... 32 9.3 Intermediate

- Term Aggregate Risk

................................ ................................ ............... 32 9.4 Chronic Aggregate Risk

................................ ................................ ................................ . 32 9.5 Cancer Aggregate Risk

................................ ................................ ................................ .. 33 10.0 Cumulative Exposure/Risk Characterization

................................ ................................ ..... 33 11.0 Occupational Exposure/Risk Characterization

................................ ................................ ... 33 11.1 Short

- Term Handler Risk

................................ ................................ ............................... 33 11.2 Short

- Term Post

- Application Risk

................................ ................................ ................ 37 11.2.1 Dermal Post

- Application Risk

................................ ................................ ................ 37 11.2.2 Inhalation Post

- Application Risk

................................ ................................ ............ 39 12.0 References

................................ ................................ ................................ .......................... 39 Attachment 1. Fluensulfone bibliography to support label amendments and new uses.

.............. 41 Appendix A. Toxicology Profile and Executive Summaries

................................ ........................ 42 A.1 Toxicology Data Requirements

................................ ................................ ..................... 42 A.2 Toxicity Profiles

................................ ................................ ................................ ............. 43 Appendix B. Physical/Chemical Properties

................................ ................................ .................. 56 Appendix C. Review of Human Research

................................ ................................ .................... 57

### Fluensulfone D427486

Page 4 of 57 1.0 Executive Summary

Fluensulfone { 5

- Chloro

- 2

- [(3,4,4

- trifluoro

- 3

- buten

- 1

- yl)sulfonyl]thiazole } is a nematicide in the fluoroalkenyl class. Fluensulfone is currently registered for use on members of the cucurbit and the fruiting vegetables crop groups (Group 9 and Group 8

- 10, respectively), and HED recently evaluated a request to register fluensulfone for use on turf and sod.

The Agen cy has received petitions from ADAMA Agricultural Solutions, Ltd. and from IR

- 4 to register a granular (G) formulation of the nematicide fluensulfone on Crop Subgroup 1B (root vegetables, except sugar beet) and Crop Subgroup 1C (tuberous and corm vegetable s), and the emulsifiable concentrate (EC) formulation on Crop Group 4 (leafy vegetables, except Brassica leafy vegetables), Crop Group 5 ( Brassica leafy vegetables), Crop Subgroup 13

- 07G (low

growing berries), Japanese white radish (daikon), turnip, and to bacco

.

In separate submissions, ADAMA has requested 1) a revision to the tolerance expression in 40 CFR 180.680 ; and 2) amend ments to the label for Fluensulfone 480EC to increase the application rate on cucurbit and fruiting vegetable crops and to change the rotational crop plant

back restriction intervals

. For both granular and EC formulations, and for all registered and requested food crops, ADAMA has proposed a single application to be made pre

- plant/pre

transplant at a maximum rate of 3.5 lb a.i./A (EC ) or 3.6 lb a.i./A (G), and the applied material is to be incorporated into the soil immediately after planting.

E xposure to fluensulfone in mammals results in effects on the hematopoietic system (decreased platelets, increased white blood cells, hematocr it, and reticulocytes), kidneys, and lungs. Changes in clinical chemistry as well as in body weight were also observed across multiple studies and species. An acute neurotoxicity screening assay showed evidence of potential neurotoxicity; however, neurotox ic effects were not observed in any other study, including a subchronic neurotoxicity study. Evidence of potential qualitative, but not quantitative, increased susceptibility of infants and children to the effects of fluensulfone was observed in the two

ge neration reproduction study in rats, in which pup loss was observed at a dose that resulted in less severe ( body weight ) effects in the dams. No evidence of either qualitative or quantitative susceptibility was observed in developmental toxicity studies in rats or rabbits. Dietary and inhalation studies in rats showed evidence of portal

- of

- entry effects in the forestomach, pharynx, epiglottis, and nasal cavity. Overall, the most sensitive endpoints for assessing human health risk are the increased pup

- loss effects for acute dietary exposure; body weight, hematological and clinical chemistry changes for chronic dietary as well as dermal exposures (short/intermediate term); and clotting time, decreased thymus weight, and portal

- of

- entry effects (histopathology of the epiglottis and nasal cavity) for inhalation exposures (short/intermediate term).

For assessing occupational oral and dermal exposures, the standard inter

- and intra

- species uncertainty factors of 10X are appropriate and result in a level of concer n (LOC) of 100. For assessing occupational inhalation exposure, the use of a reference concentration for humans (RfC) supports reducing the interspecies factor to 3X; however, an additional 10X factor is required because a no

- observed

- adverse

- affect level (NOAEL) was not found for the portal

- of

entry effects, resulting in an LOC of 300. Given the different endpoints at the regulatory points of departure for the dermal and inhalation routes of exposure, risk estimates from these two

### Fluensulfone D427486

Page 5 of 57 routes were not combined. Based on the completeness of the toxicity data, the use of the most sensitive endpoints for risk assessment and the resulting low degree of concern regarding the observed qualitative susceptibility, and the conservatisms in the exposure assessments, HED h as reduc ed the required Food Quality Protection Act Safety Factor (FQPA SF) from 10X to 1X.

The proposed new uses are supported by adequate residue data. Quantifiable r esidues of the BSA metabolite, which is the residue defined for enforcement, are expec ted in all food and feed commodities following treatment with fluensulfone. Residues of fluensulfone per se , which is the residue defined for assessing risk, were below the limit of quantification (LOQ; 0.01 ppm) in all field trial results except those fro m carrot, celery, head lettuce, and leaf lettuce. HED has evaluated dietary exposure to fluensulfone, taking into account all registered and proposed uses and estimated residues in drinking water from those uses ( D 432134

, 29 March 2016

, J

. Cowins ). Dietary (food and water) risk estimates for fluensulfone are not of concern for both acute and chronic exposure durations.

In order to assess the requested application rates, HED evaluated the originally submitted field trials for cucurbit and fruitin g vegetables; ADAMA’s proposed revised endpoint and dose for dermal risk assessment, including a revised dermal absorption factor (DAF) derived from new studies; and an occupational chemigation survey conducted by ADAMA to support a proposed revision to th e assumption for the number of acres treated for occupational mixer/loaders. For the rotational crop plant

- back restrictions, HED reviewed data from field rotational crop studies submitted with the request. The available data support the requested applicat ion rates for all crops, but do not support the requested rotational crop plant

- back intervals.

The use of fluensulfone on turf may result in short

- term residential exposures for persons present in treated areas after application (i.e., post

- application). Routes of exposure are dermal for post

application activities for adults, youth and children, and incidental oral (post

- application) for children only. Due to changes in toxicological points of departure for the dermal route of
exposure , HED reassessed re sidential exposure and risk as part of this risk assessment. Residential risk estimates for fluensulfone are not of concern for adults and children engaged in post

- application activities on treated turf

. Further, a ggregate risk estimates from combined derm al and oral exposures, including food and drinking water sources, are not of concern.

For occupational scenarios, long

- term exposures (> 6 months) are not expected to occur; however, short

- term (1

- 30 days) and intermediate

- term (1

- 6 months) exposures may occur. With the use of the submitted chemigation survey data, there are no dermal risk estimates of concern for mixer/loaders for chemigation; in addition, there are no dermal risk estimates of concern for the proposed new uses

. For both formulations, HED identified potential occupational mixer/loader/applicator inhalation risk estimates below the level of concern ( LOC, i.e., margins of exposure ( MOEs ) < 300) for most scenarios with no respirators. There is no label

recommended personal protective equipmen t ( PPE ) for respiratory protection

. Mitigation through the use of respirators or engineering controls achieved MOEs of greater than or approximately equal to the LOC of 300 . Dermal risk estimates were not of concern for all scenarios, including handler and post

- application scenarios , at the label

- recommended attire and PPE (i.e., long

- sleeved shirts, long pants, shoes plus socks and chemical

- resistant gloves)

.

### Fluensulfone D427486

Page 6 of 57 Potential areas of environmental justice concerns were considered in this human health risk

asses sment to the extent possible. For more information, see Section 3.5.

This risk assessment relies in part on data from studies in which adult human subjects were intentionally exposed to a pesticide or other chemical. Those studies are subject to ethics re view, have received that review, and are compliant with applicable ethics requirements.

The most recent risk assessment for fluensulfone was conducted in 201 6 (D4 24168

, 6 January 201 6 , M. Doherty et al.) , to support a proposed use on turf

.

2.0 HED Recommendations

HED has identified some occupational exposure scenarios with MOEs below the LOC. Th e MOEs can be mitigated with the addition of PPE. Provided RD ensures that appropriate PPE is specified on the subject labels, t here are no human health ri sk issues that would preclude granting the requested label amendments, changing the established tolerance definition, or establishing new tolerances on the requested commodities. Specific recommendations are discussed in the sections below.

2.1 Data Defic iencies

None.

2.2 Tolerance Considerations

HED has reviewed the petitioned

- for tolerances and changes to established tolerances, and has recommended appropriate tolerance levels in Table 2.2.2.

The request to change the tolerance expression is accepta ble. HED is recommending the tolerance expression in 40 CFR 180.680(a) be changed to remove the stipulation that compliance be in terms of fluensulfone; to wit: (a) General. Tolerances are established for residues of the nematicide fluensulfone, including its metabolites and degradates, in or on the commodities in the table below. Compliance with the tolerance levels specified below is to be determined by measuring only 3,4,4

- trifluoro

- but

- 3

- ene

- 1

- sulfonic acid.

The change in the tolerance expression would result in a decrease in tolerance levels for the existing tolerance listings by a factor of 1.5. However, due to the concomitant increase in the application rate by a relative factor of 1.4 and the rounding within the OECD MRL calculation procedures, the net result is that the existing tolerance levels for residues in cucurbit vegetables (Crop Group 9) and fruiting vegetables (Crop Group 8

- 10) should not be changed despite the change in the tolerance expression.

Furthermore, HED notes that the time

- limite d tolerance associated with the Section 18 use on carrot ( 40 CFR 180.680(b) ) should be removed upon establishment of a permanent tolerance for residues of fluensulfone in or on Crop Group 1B , which includes carrot

.

### Fluensulfone D427486

Page 7 of 57 2.2.1 Enforcement Analytical Method

An acceptable analytical method for enforcement was evaluated with the initial fluensulfone submission. That method uses acetonitrile/water (1:1, v/v) extraction and analysis by reverse

phase HPLC

- MS/MS. For analysis of the BSA metabolite ( 3,4,4

- trif luoro

- but

- 3

- ene

- 1

- sulfonic acid), which is the sole analyte for enforcement purposes, there is no clean

- up in the method aside from filtration. The limit of quantification (LOQ), defined as the lowest limit of method validation, is 0.01 ppm. That same method was us ed to analyze all samples related to the current petitions. Based on concurrent recoveries, the method is deemed adequate for tolerance enforcement for the new use commodities.

2.2. 2 Recommended Tolerances

Table 2.2.2

. Tolerance Summary for Fluensulfone

. Commodity Established/ Proposed Tolerance (ppm) HED

Recommended Tolerance (ppm) Comments

( correct commodity definition )

Revision due to Change in Toleran ce Expression and Rate Increase Vegetables, cucurbits, group 9 0.5 0 0.5 0 No numerical change Vegetables, fruiting, group 8

- 10 0.5 0 0.5 0 No numerical change Tomato, paste 1.0 1.0 No numerical change New Uses (Petitions 5F8351 and 5E8384) Root vegetables, subgroup 1B, except sugar beet and oriental radish 3.3 3 .0 Vegetables, r oot , except sugar beet

, subgroup 1B Radish, oriental 0.50 None Oriental radish is a member of crop subgroup 1B. Leaves of Root and Tuber Vegetables , group 2 2 0 30 Vegetables, leaves of root and tuber, group 2, except sugar beet Vegetable, tuberous and corm 0.6 0.5 0 Vegetables, tuberous and corm, subgroup 1C Potato granules/flakes Not proposed 0.8 0 Potato, granules/flakes Potato chips Not proposed 0.6 0 Potato, chips Leafy Vegetables , group 4, e xcept Brassica Vegetables) 2.6 2 .0 Vegetables , leafy, except Brassica

, Group 4 Head and Stem Brassica subgroup 5A 1.3 1

. 50 Brassica, head and stem, subgroup 5A Leafy Brassica greens subgroup 5B 13 9 .0 Brassica, leafy greens, subgroup 5B Berry, low growing, subgroup 13

- 07G 0. 3 0.3 0 Berry, low growing subgroup 13

- 07G



### 2.2. 3 Revisions to Petitioned

- For Tolerances

Most of the petitioned

- for tolerance levels differ from those being established by the Agency. In the cases of the tolerances proposed by ADAMA, it is not clear to the Agency how the tolerance levels p roposed in the 16 March 2016 notice of filing (Federal Register 2016

- 05952) were derived. EPA’s tolerance levels are based on residues of BSA only, without any conversion to fluensulfone equivalents. The Agency used the OECD MRL procedures to derive the le vels being established in today’s action. For crop groups, and per EPA’s current policy, tolerance

### Fluensulfone D427486

Page 8 of 57 levels for each representative commodity were calculated separately, and then the maximum value within each crop group was selected as the tolerance level. F or root vegetables except sugar beet (Subgroup 1B), the tolerance level is based on data from radish root (including Oriental radish root). Although a separate listing for Oriental radish was requested, EPA is not establishing a separate tolerance level si nce that crop is a member of crop subgroup 1B. For leaves of root and tuber vegetables (Crop Group 2), EPA is establishing a tolerance for residues in/on the leaves of root and tuber vegetable, except sugar beet because the petitioned

- for uses do not inclu de a use on sugar beet; the tolerance is based on data from radish tops (including Oriental radish tops). The tolerance for residues in/on leafy vegetables except Brassica vegetables (Group 4) is based on data from leaf lettuce and spinach, assessed separa tely. For head and stem Brassica (Subgroup 5A), the tolerance is based on data from cabbage. For Brassica leafy greens (Subgroup 5B), data from mustard greens, komatsuna (Japanese mustard spinach), and mizuna (Japanese mustard) were combined to derive the tolerance level. Finally, the EPA’s tolerance level for residues in/on low growing berries (Subgroup 13

- 07G) is based on residue data from strawberry. All of EPA’s tolerance levels are expressed to provide sufficient precision for enforcement purposes, and this may include the addition of trailing zeros (e.g., 0.30 ppm rather than 0.3 ppm).

In the case of the tolerance proposed by IR

- 4, the petitioned

- for tolerance is based on the sum of residues of BSA and TSA, expressed as fluensulfone, rather than on re sidues of BSA only, which is how the Agency regulates residues of fluensulfone. Basing enforcement on BSA alone provides a suitable marker of use, simplifies residue analysis, and avoids complications that may result from the potential for TSA to carry ove r in treated soil from one year to the next. Furthermore, IR

- 4 did not propose tolerances for residues of fluensulfone in processed potato commodities. The submitted potato processing study indicates that during processing, residues of BSA in chips and in granules/flakes are likely to concentrate to levels greater than in tubers. Therefore, EPA is establishing separate tolerances to cover residues in those commodities.

2.2. 4 International Harmonization

The current tolerance expression for fluensulfone (4 0 CFR 180.680) specifies that compliance “...is to be determined by measuring only 3,4,4

- trifluoro

- but

- 3

- ene

- 1

- sulfonic acid, calculated as the stoichiometric equivalent of fluensulfone.” The registrant has petitioned the Agency to revise the tolerance expre ssion to be in terms of 3,4,4

- trifluoro

- but

- 3

- ene

- 1

- sulfonic acid , the BSA metabolite, per se in order to harmonize with the residue definition established by Codex. In addition, the registrant has petitioned the Agency to increase the application rate for use on cucurbit and fruiting vegetables from 2.5 lb ai/A to 3.5 lb ai/A. HED has re

- examined the data from the cucurbit and fruiting vegetable field trials, which were conducted at an application rate of 3.5 lb ai/A. There is no numerical change to the es tablished tolerance levels for those groups due to the offsetting increase from the rate change (3.5 lb ai/A ÷ 2.5 lb ai/A = 1.4) and the decrease from the removal of the stoichiometric conversion ( 291.7 g/mol fluensulfone ÷ 190.1 g/mol BSA = 1.5 ) , and the rounding classes used in the OECD MRL calculation procedures

. Maximum residue levels (MRLs) have been established by Canada and Codex for residues of fluensulfone in cucurbit vegetables (0.6 ppm Canada; 0.3 ppm Codex), fruiting vegetables (0.5
ppm Canada; 0.3 ppm Codex), and tomato paste (1.0 ppm Canada; 0.5 ppm Codex) . There is a

### Fluensulfone D427486

Page 9 of 57 lack of harmonization with the Canadian MRLs due to differences in the residue definition and to the new, higher application rate, and with the Codex MRLs due to the new a pplication rate.

2.3 Label Recommendations

2.3.1 Recommendations from Residue Reviews

RD should ensure that the following issues with the labels are resolved (see D 427502, J. Cowins, 31 March 2016 for details) :

 EC and G Labels

. The registrant has reques ted that the rotational crop plant

- back restrictions be amended to specify a plant

- back interval (PBI) of 180 days for root and grain crops and 150 days for all other crops not on the label. The submitted data do not support that request and the plant

- back restriction should remain at 365 days ; moreover, the data indicate that a restriction specifying no rotation to cereal grains is required. Thus, HED is recommending that the rotational crop restriction s on both the EC and G labels for fluensulfone allow i mmediate plant

- back to crops on either label (Crop Groups/Subgroups 1B, 1C, 4, 5, 8

- 10 , 9, and 13

- 07G), a prohibition against rotating to cereal grains after treatment with either the EC or the G formulations , and 365

- day restriction for all other crops.

 EC Label

. Japanese mustard spinach and hot herb mustard are included in Crop Group 5 and the use directions for those crops and that crop group are identical; therefore, the individual listings for Japanese mustard spinach and hot herb mustard can be removed from the label. Furthermore, there is no codified crop group called “Japanese Root Vegetables;” therefore, HED is recommending that the EC label be revised to remove reference to “Japanese Root Vegetables.” The individual listings for turnip and Ja panese white radish (daikon) should remain on the label.

 EC Label . U nder the headings for broadcast application and banded application, the proposed label specifies pre

- plant and pre

- seeding intervals of 7 and 14 days. Those directions are in conflict wit h those in the crop

- specific use directions for Brassica (cole) leafy vegetables, Japanese mustard spinach, hot herb mustard spinach, Japanese white radish (daikon), and turnip, which specify that treatment occur a minimum of 30 days prior to transplanting or seeding. The language in the general use information section should be revised to correct the inconsistency.

 G Label . For the crop

- specific use directions, the directions for potato, sweet potato, yam, and others give a crop group of “ROOT VEGETABLES (EXCEPT SUGAR BEET) SUBGROUP 1

- C.” The correct name for Crop Subgroup 1C is “Tuberous and Corm Vegetables ,” and the label should be revised accordingly.

2.3.2 Recommendations from Occupational Assessment

The proposed EC and G fluensulfone labels require handlers to wear baseline attire (i.e., long

sleeved shirt, long pants, shoes plus socks) and PPE (i.e., chemical

- resistant gloves). In addition, the G label requires a PF10 respirator for operators of tractor

- drawn spreaders. For both

### Fluensulfone D427486

Page 10 of 57 formulations, inhala tion MOEs are below the level of concern of 300 for many scenarios. For the majority of those cases, addition of a PF5 respirator results in MOEs greater than 300. For one scenario with the granular formulation (mixer/loader for tractor

- drawn spreader for high

- acreage crops), the addition of a PF10 respirator results in an MOE of 270; engineering controls are needed to obtain an MOE greater than 300 for this scenario. RD should ensure that appropriate personal protect ive equipment (PPE) is included on the l abel s to protect occupational handlers (i.e., PF5 or PF10 respirator , or engineering controls ). Information to assess the dry bulk fertilizer use was not provided, and that use should be removed from the label. Furthermore, RD should ensure that the restri cted

- entry interval (REI) appears on the labels. The toxicology categories for fluensulfone indicate that a 12

- hour REI is appropriate.

HED notes that c losed systems are no longer required on the EC formulation label for mixing and loading activities for chemigation applications in order to mitigate handler exposure.

2.3.3 Recommendations f rom Residential Assessment

None

3.0 In troduction

Fluensulfone is a non

- fumigant nematicide and the first active ingredient in the fluoroalkenyl class of pesticides

. Fluensulfone shows activity in multiple nematicide physiological systems; its specific pesticidal mode of action is not known at this time.

3.1 Chemical Identity

Table 3.1. Fluensulfone Nomenclature. Compound Chemical Structure

Common name Fluensulfone Company experimental name MCW

- 2 IUPAC name 5

- chloro

- 1,3

- thiazol

- 2

- yl 3,4,4

- trifluorobut

- 3

- en

- 1

- yl sulfone CAS name 5

- chloro

- 2

- [(3,4,4

- trifluoro

- 3

- buten

- 1

- yl)sulfonyl]thiazole CAS # 318290

- 98

- 1 End

- use product/EP 66222

- 243

– Emulsifiable Concentrate (40% a.i.), 66222

- EAE

– Granular (15% a.i.) Compound

BSA Chemical Structure

### Fluensulfone D427486

Page 11 of 57 IUPAC name 3,4,4

- trifluoro but

- 3

- ene

- 1

- sulfonic acid CAS name 3,4,4

- trifluoro

- but

- 3

- ene

- 1

- sulfonic acid



### 3.2 Physical/Chemical Characteristics

Technical

- grade fluensulfone is solid at room temperature, however a phase change (from solid to liquid) may occur at elevated temperatures

. The chemical is slightly volatile (vapor pressure = 0.03 Pa at 25°C); therefore exposure to fluensulfone in its vaporous phase is l ikely. The technical

- grade substance has a log K OW 

### of 2.2 indicating a relatively lipophilic nature, but not to a degree that soil adsorption and bioaccumulation should be of concern.

Dietary exposure to the metabolites BSA and TSA is expected to be great er than that to the parent compound, fluensulfone. Physicochemical properties for BSA and TSA were not provided. As sulfonic acids, which are considered to be strong acids that exist as salts, these metabolites are expected to be more hydrophilic , more mob ile in the soil profile, and lower in volatility, relative to the parent compound

.

3.3 Pesticide Use Pattern

T wo formulations are being considered for the new uses of fluensulfone: a new granular formulation

, containing 15% a.i.

, for use on root vegetab les (except sugar beet; Crop Subgroup 1B) and tuberous and corm vegetables (Crop Subgroup 1C), and a currently registered emulsifiable concentrate

, containing 40% a.i. , for use on leafy vegetables (Crop Group 4), brassica vegetables (Crop Group 5), low

- gro wing berries (Crop Subgroup 13

- 07G), Japanese white radish (daikon), turnip, and tobacco. For all uses, the annual maximum application rate is 3.5 lb ai/A.

Table 3.3. Summary of Proposed Directions for Use of Fluensulfone.

Applic. Timing, Type, and Equip. Formulation

[EPA Reg. No.] Applic.

Rate (lb ai/A) Max.

No. Applic.
per Season Max. Seasonal

Applic. Rate (lb ai/A) Applic.

Timing Use Directions

and Limitations

LABEL AMENDMENTS Cucurbit Vegetables (Crop Group 9 includes: cucumbers, melons (cantaloupes, watermelon, honeydew), and squash.) Fruiting Vegetables (Crop Group 8

- 10 includes: bell pepper, eggplant, ground cherry, hot pepper, pepino, pepper

(except black), pimento, sweet pepper, tomatillo, and tomatoes for processing.)

Pre

- Plant; D rip irrigation, Band applicator, Broadcast
spray Emulsifiable

Concentrate [66222

- 243 ] 1.75

- 3.50

lb ai/A (56

- 112 fl oz/A) 1

- 2

(depend ing on rate) 3.5 lb ai/A Apply at least 7 days before transplanting and at least 14 days before seeding For pre

- seeding

applications,

m ake 2 supplemental irrigations prior to planting

.

Do not rotate to cereal grains. For crops not on either the EC label or the G label, do not plant

### Fluensulfone D427486

Page 12 of 57 back for 180 days following application NEW USES Root vegetables (except sugar beet) Subgroup 1B

– carrot, radish, turnip and other root vegetables including: Beet, garden; burdock, edible; celeriac; chervil, turnip

- rooted; chicory; ginseng; horseradish; parsley, turnip

rooted; parsnip; radish, oriental; rutabaga; salsify; salsify, black; salsify, Spanish; skirret

Pre

- plant: broadcast or band treatment to soil Granule

[66222

- EAE] 1.78

– 3.6

lb ai/A

[2.0

– 4.0 kg ai/ha] 1

appl./yr 3.6 lb ai/A

[4.0 kg ai/ha] Apply at

least 10 days before planting for seeded crops. Do not allow

livestock animals to forage/graz e within 6 months.

Do not rotate to cereal grains. For crops not on either the EC label or the G label, do not plant back for 180 days following application Tuberous and corm Subgroup 1C

– potato and other root vegetables including : arracacha; arrowroot; artichoke, Chinese; artichoke, Jerusalem; canna, edible; cassava, bitter and sweet; chayote (root); chufa;

dasheen; ginger; leren; potato; sweet potato; tanier; turmeric; yam bean; yam, true

Pre

- plant: incorporation, broadcast, or banding to soil Granule

[66222

- EAE] 1.78

– 3.6

lb ai/A

[2.0

– 4.0 kg ai/ha] 1

appl./yr 3.6 lb ai/A

[4.0 kg ai/ha] A pply at

planting or
pre

- planting. Do not allow

livestock animals to forage/graz e within 6 months.

Do not rotate to cereal grains. For

cr ops not on either the EC label or the G label, do not plant back for 180 days following application Leafy Vegetables (Except Brassica Vegetables), Group 4

– Celery, lettuce (head and leaf), spinach and other leafy vegetables including: Amaranth; arugula; chervil; chrysanthemum, edible

- leaved; chrysanthemum, garland; corn salad; cress, garden; cress, upland; dandelion; dock; endive; lettuce; orach; parsley; purslane, garden; purslane, winter; radicchio (red chicory); spinach; spinach, New Zealand; spinach, vine.

Pre

- plant: broadcast spray, band application, or Drip irrigation Emulsifiable

Concentrate [66222

- 243] 1.75

– 3.5

lb ai/A

(56

– 112 fl. oz./A)

[1.92

- 3.84 kg ai/ha] 1

appl./yr 3.5 lb ai/A

(112 oz./A)

[3.84 kg ai/ha] Apply at

least 7 days prior to transplanting and at least 14 days prior to seeding. Do not rotate to

cereal grains. For crops not on either the EC label or the G label, do not plant back for 180 days following application Japanese white radish (daikon)

Turnip

### Fluensulfone D427486

Page 13 of 57 Brassica (COLE) leafy vegetables Group 5

– Broccoli, cabbage, cauliflower and other brassicas including: broccoli, Chinese (gai lon); broccoli raab (rapini); Brussel sprouts; cabbage, Chinese (bok choy); cabbage Chinese (napa); cabbage Chinese mustard (gai choy); cavalo broccoli; collards; kale; kohlrabi; mizuna; mustard greens; mustard spinach; rape greens

Pre

- plant: broadcast spray, band application, or Drip irrigation Emulsifiable

Concentrate [66222

- 243] 1.75

– 3.5

lb ai/A

(56

– 112 fl. oz./A)

[1.92

- 3 .84 kg ai/ha] 1

appl./yr 3.5 lb ai/A

(112 oz./A)

[3.84 kg ai/ha] Apply at

least 30 days prior to transplanting or seeding. Do not rotate to

cereal grains. For crops not on either the EC label or the G label, do not plant back for 180 days following application Berry and Small Fruit, Subg roup 13

- 07 G

– Strawberry and Low growing berry including: Bearberry; bilberry; blueberry, lowbush; cloudberry; cranberry; lingonberry; muntries; partridgeberry; strawberry; cultivars, varieties, and/or hybrids of the se

Pre

- plant: broadcast spray, band application, or Drip irrigation Emulsifiable

Concentrate [66222

- 243] 1.75

– 3.5

lb ai/A

(56

- 112 fl. oz./A)

[1.92

- 3.84 kg ai/ha] 2

appl./yr 3.5 lb ai/A

(112 oz/A)

[3.84 kg ai/ha] Apply at

least 7 days before planting.

For all perennial
crops, application may be split between spring and fall. The spring application must be made 30 days or more prior to bloom and the fall application must be made after harvest. Do not rotate to

cereal grains. For crops not on either the EC label or the G label, do not plant back for 180 days following application

Tobacco

Pre

- plant: broadcast spray, band application, or Drip irrigation Emulsifiable

Concentrate [66222

- 243] 1.75

– 3.5

lb ai/A

(56

– 112 fl. oz./A)

[1.92

- 3.84 kg ai/ha] 1

appl./yr 3.5 lb ai/A

(112 oz/A)

[3.84 kg ai/ha] Apply at

least 7 days before planting. Do not rotate to

cereal grains. For crops not on either the EC label or the G label, do not plant back for 180 days following application



### Based on the review of the submitted residue data ( J. Cowins, 31 March 2016 . D 427502 ), HED is recommending the following changes to the labels:

### Fluensulfone D427486

Page 14 of 57  Rotational crop restrictions on both the EC and G labels for fluensulfone allow immediate plant

- back to crops o n either label (Crop Groups/Subgroups 1B, 1C, 4, 5, 8

- 10, 9, and 13

- 07G), a prohibition against rotating to cereal grains after treatment with either the EC or the G formulations, and 365

- day restriction for all other crops.

 Japanese mustard spinach and hot herb mustard are included in Crop Group 5 and the use directions for those crops and that group are identical; therefore, the individual listings for Japanese mustard spinach and hot herb mustard can be removed from the EC label.

 “Japanese Root Vegeta bles” are not a codified crop group; therefore, t he EC label should be revised to remove reference to “Japanese Root Vegetables.” The individual listings for turnip and Japanese white radish (daikon) should remain on the label.

 The pre

- plant intervals on the EC label in the general use directions section should be revised to be not in conflict with the intervals specified for Brassica (cole) leafy vegetables, Japanese white radish (daikon), and turnips.

 The name of Crop Subgroup 1C on the label for the gr anular formulation is incorrect and should be revised to say “Tuberous and Corm Vegetables Subgroup 1C.”

3.4 Anticipated Exposure Pathways

Use of fluensulfone on food crops may result in human exposures to residues via food and drinking water (as a result of transport of residues into ground and surface water drinking water supplies). In addition, the use of fluensulfone on turf ( registration pending) may result in dermal, inhalation, and oral exposures in a residential setting . From an occupational perspective, workers may be exposed (dermal and inhalation) to fluensulfone during mixing, loading, and/or applying the pesticide. Post

- application occupational exposures may also occur when workers re

- enter treated fields.

This risk assessment considers all of these exposure pathways, taking in to account the registered and proposed uses of fluensulfone.

3.5 Consideration of Environmental Justice

Potential areas of environmental justice concerns, to the extent possible, were considered in this human hea lth risk assessment, in accordance with U.S. Executive Order 12898, "Federal Actions to Address Environmental Justice in Minority Populations and Low

- Income Populations," ( http://www.e h.doe.gov/oepa/guidance/justice/eo12898.pdf

. As a part of every pesticide risk assessment, OPP considers a large variety of consumer subgroups according to well

- established procedures

. In line with OPP policy, HED estimates risks to population subgroups fr om pesticide exposures that are based on patterns of that subgroup’s food and water consumption, and activities in and around the home that involve pesticide use in a residential setting

. Extensive data on food consumption patterns are compiled by the USDA under the Continuing Survey of Food Intake by Individuals (CSFII) and are used in pesticide risk assessments for all registered food uses of a pesticide

. These data are analyzed and categorized by subgroups based on age,

### Fluensulfone D427486

Page 15 of 57 season of the year, ethnic group, and region of the country

. Additionally, OPP is able to assess dietary exposure to smaller, specialized subgroups and exposure assessments are performed when conditions or circumstances warrant

. Whenever appropriate, non

- dietary exposures based on home use of pesticide products and associated risks for adult applicators and for toddlers, youths, and adults entering or playing on treated areas post

- application are evaluated

. Further considerations are currently in development as OPP has committed resources a nd expertise to the development of specialized software and models that consider exposure to bystanders and farm workers as well as lifestyle and traditional dietary patterns among specific subgroups.

4.0 Hazard Characterization and Dose

- Response Assessme nt

4.1 Summary of Toxicological Effects

The toxicology database for fluensulfone is complete and acceptable for selecting toxicity endpoints and points of departure for risk assessment

. The toxicology database includes a recently submitted in vitro comparative dermal absorption study with rat and human skin for the EC formulation to refine the dermal absorption value that was evaluated as part of the last risk assessment (D424168)

. In addition, a submission from the registrant to consider an alterna tive dermal POD was evaluated as part of this risk assessment ( D429722 ) and taken into consideration for endpoint selection (see section 4.5.1).

The available toxicology studies include the following:

 subchronic oral toxicity studies in rats, mice and dogs

 28

- day dermal toxicity study in rats

 90

- day inhalation study in rats

 developmental toxicity studies in rats and rabbits

 2

- generation reproduction study in rats

 chronic toxicity studies in rats and dogs

 carcinogenicity studies in mice and rats

 battery of genotoxicity studies

 dermal penetration study in rats and two in vitro comparative dermal absorption study with rat and human skin (all three testing an EC formulation of fluensulfone)

 acute and subchronic neurotoxicity studies in rats

 an immun otoxicity study in mice

 multiple ADME studies in rats

 acute oral, dermal, and inhalation toxicity studies

 primary eye and dermal irritation studies

 a dermal sensitization study

For the BSA and TSA metabolites of fluensulfone, toxicology studies include:

 acute oral studies in rats

 28

- day oral studies in rats

 b acterial and mammalian cell mutagenicity studies

### Fluensulfone D427486

Page 16 of 57 4.2 Absorption, Distribution, Metabolism, & Elimination (ADME)

In rats, fluensulfone is rapidly absorbed following oral dosing

. The time to maximum plasma levels (t max 

### ) was 2

- 4 hours in males and females at the low dose (5 mg/kg) and 1

- 8 hours at the high dose (500 mg/kg/day). The time to maximum whole blood levels (t max 

### ) was longer at 2

- 8 hours at the low dose and 48 hours at the high dose. The diffe rence in whole blood and plasma
t max 

### is related to fluensulfone reacting with the free thiol moiety of globin in the erythrocyte. The majority of the dose was absorbed, as indicated by recovery of about 85% of the applied dose in the urine (including cage wash) at both doses tested (5 and 500 mg/kg), suggesting that there was no saturation of absorption

. Urine was the major route of excretion accounting for 75

- 88% of the administered dose (AD) with feces accounting for 5

- 13% AD

. Most of the AD (~80%) was

ex creted during the first 24 hours at the 5 mg/kg dose level

. Fluensulfone

- related compounds did not accumulate in tissues; the total residual radioactivity in tissues/organs was ~3.1% AD at 51 hours post

- dosing

. The highest tissue levels were observed in th e liver, kidney, and gastrointestinal tract

. Identification of compounds in the urine (Table 4.2) showed no parent fluensulfone and indicates that fluensulfone cleaves at the sulfonyl bridge

. The metabolic pathway begins with fluensulfone reacting with glu tathione to displace butene sulfinic acid which is then oxidized to BSA

. The glutathione adduct of the thiazole ring can then be cleaved to the cysteine conjugate, which is acetylated to the mercapturate

. The glutathione ring is also cleaved to thiazole th iol (not detected in metabolism studies), which can either be oxidized to TSA or conjugated with glucuronic acid to give the two glucuronides

. No major sex

- related differences were observed in absorption, distribution, metabolism, or excretion.

Table 4.2

. Summary of Compounds in Rat Urine Following Dosing with 14 C

- Fluensulfone. Chemical Identity % of Applied Dose Butene

- Radiolabel Thiazole

- Radiolabel 5 mg/kg 500 mg/kg 5 mg/kg 500 mg/kg Fluensulfone ≤ 0.1 ≤ 0.1 ≤ 0.1 ≤ 0.1 Butene sulfinic acid 32

- 35 53

- 57

-- -- Butene sulfonic acid (BSA) 4

- 5 4

-- -- Thiazole mercapturate

-- -- 38

- 40 49

- 54 Thiazole glucuronide I and II

-- -- 24

- 27 20

- 22 Thiazole sulfonic acid (TSA)

-- -- 3

- 5 1

- 3

-- = this metabolite was not detectable because it did not contain the radiolabel.



### 4.2.1 Dermal Absorption

Previously , a dermal absorption value was calculated using the results from an in vivo dermal absorption study (MRID 48574949) with the EC formulation refined by the results from an in vitro dermal absorption study with the EC formulation using rat and human skin (MRID 48574950). T he registrant submitted a second in vi tr o dermal absorption study with the EC formulation using rat and human skin (MRID 49700504) because they felt that a number of the conditions in the original study led to an overestimation of dermal absorption including: the occlusive nature of the application, the use of a 24

- hour exposure period, and the use of an
org anic

- solvent

- based receptor fluid. In contrast, the newly submitted in vitro study w as not occlusive, exposed the skin for only 8 hours, and used physiological saline as a receptor fluid. These parameters are in line with the OECD test guideline 428 for in vitro dermal absorption

### Fluensulfone D427486

Page 17 of 57 studies and more closely represent worker exposure conditio ns. Therefore, the newly submitted dermal absorption study is considered more relevant for risk assessment and was used to refine the in vivo dermal absorption value. The dermal absorption value determined with rat skin in the

new ly submitted study was considerably lower (43.6%) than that determined in the previous study (93.5%)

. The data demonstrated an inverse relationship between dosing concentration and percent absorption

. Based on in vivo dermal absorption observed in the rat and in vitr o comparative rat:human absorption data from the newly submitted study, an estimated human dermal absorption factor (DAF) of 9.5% was obtained as follows (all absorption values adjusted for recovery):

(1) In the rat in vivo dermal absorption study, a der mal absorption of 58.0% (directly absorbed plus absorbable) was found at 24 hrs post

- exposure using an application of 0.0953 mg/cm 2 

### ; (2) I n vitro exposure of split

- thickness rat skin under the same exposure and assessment conditions gave a dermal absorpti on of 43.6% (directly absorbed plus absorbable); (3) The ratio of the rat in vitro to the rat in vivo absorption is 0.75 (43.6/58.0) which is close to 1, indicating that the in vitro data is predictive of in vivo absorption; (4) Based on this ratio, a DA F for humans may be calculated using in vitro human dermal absorption (7.1%, directly absorbed plus absorbable) observed in vitro under the same exposure conditions

. The DAF for humans is therefore 7.1%/0.75= 9.5%.

4.3 Toxicological Effects

The hematopoietic system was the major target of fluensulfone across multiple species with effects seen in rats, dogs, and mice

. Effects on the hematopoietic system included decreased mean corpuscular hemoglobin, decreased mean corpuscular hemoglobin conce ntration, decreased hemoglobin, increased reticulocytes, and increased hemoglobin distribution width suggestive of hemolytic anemia. The hematological changes observed in the rat and dogs were consistent with a modest hemolytic effect of the chemical and c onsidered minimally adverse. The effects appeared to be well

- compensated and likely to not have a measureable effect on
oxygen

- carrying capacity under normal conditions. However, since it appeared the functional RBC capacity was reduced and therefore, it i s plausible that there would be an effect on RBC function under lower

- oxygen conditions or the ability of bone marrow to respond to future regenerative demand

. While dogs appeared to be the most sensitive species in terms of effects on the hematopoietic sy stem when directly comparing the NOAELs and LOAELs, effects in rat and dogs occurred at similar human equivalent doses following 3⁄4 body weight scaling (see section 4.5.1 for more detail). The e ffects on the hematopoietic system are consistent with results from rat metabolism studies which demonstrate that fluensulfone can react with the free thiol moiety of globin, forming a covalent linkage to the thiazole group displacing butene sulfinic acid

. This led to slower elimination of the thiazole portion of flue nsulfone from whole blood (time from dose to 50% of peak concentration, DT 50 

### = 6

- 9 days) compared to plasma (DT 50 

### = 16

- 17 hours).

Other effects commonly observed in mice, rats, and dogs included changes in clinical chemistry parameters and decreased body weights, both of which were often seen at the LOAELs in

### Fluensulfone D427486

Page 18 of 57 subchronic and chronic studies

. Altered clinical chemistry parameters included decreased plasma alanine amino transferase (ALAT, rats and dogs), increased cholesterol (rats), increased triglycerides ( rats), increased phospholipids (rats), increased (mice) or decreased (dogs) bilirubin, decreased protein (dogs), decreased albumin and albumin/globulin ratio (dogs), decreased glucose (dogs), and increased TSH (dogs) in subchronic studies

.

Fluensulfone also caused effects on the kidney in male rats; however, the effects are consistent with accumulation of α

- 2

- microglobulin in the kidneys which is a male rat specific process that is not relevant for human health risk assessment (USEPA 1991).

Effects on t he lung were observed following chronic dietary exposure in mice and rats

. These effects consisted of an increased incidence and severity of lung interstitial inflammation in the 2

- year rat study and an increased incidence of bronchiolization (change from flattened epithelium to cubodial epithelium) in the 18

- month mouse study

. Furthermore, an increased incidence of lung adenomas and carcinomas were observed following c hronic dietary exposure to fluensulfone in female mice

. Fluensulfone also appeared to ca use portal

- of

- entry effects in rats

. This included the forestomach (diffuse basal cell hyperplasia) and pharynx (mononuclear infiltrates) in dietary subchronic studies; the epiglottis (squamous metaplasia, epithelial hyperplasia, and focal mononuclear cell infiltrates) and nasal cavity (squamous epithelial hyperplasia) in the 90

- day inhalation study; and an increased incidence/severity of acanthosis/hyperkeratosis in the 28

- day dermal study

. The dermal effects were considered adaptive due to the moderate de gree of acanthosis/hyperkeratosis observed.

Following a single oral administration, rats exhibited decreased locomotor activity, decreased spontaneous activity, decreased rearing, and impaired righting response only on Day 1 in the acute neurotoxicity stu dy

. No evidence of neurotoxicity was observed in any other study, including a subchronic neurotoxicity study

. Following dermal exposure for 28

- days, systemic effects including increased reticulocytes, and increased cholesterol were observed, but only at a very high dose (2000 mg/kg/day, which is twice the highest dose required by the guidelines for a dermal study)

. There was no evidence of immunotoxicity in the mouse

. No evidence of increased quantitative or qualitative susceptibility was seen in developm ental toxicity studies in rats and rabbits

. In the rat developmental toxicity study, decreased fetal weight was observed in the presence of decreased body weight in maternal animals

. In the rabbit developmental toxicity study, decreased fetal weight and in complete ossification of digit 5 of the medial phalanx in both forelimbs were observed in the presence of decreased body weight in maternal animals

. In the two generation reproduction study, there was no evidence of quantitative susceptibility; evidence fo r qualitative susceptibility was manifested as decreased pup weight, decreased spleen weight, and an increase in post

- natal pup loss [post

- natal days (PND) 1

- 4] which were seen at the same dose that caused decreases in body weight in the parental animals.

All genotoxicity studies that were conducted on fluensulfone and three of its metabolites (thiazole sulfonic acid; TSA, butene sulfonic acid; BSA, and methyl sulfone; MeS) were

### Fluensulfone D427486

Page 19 of 57 negative, except for MeS with Salmonella typhimurium strain TA 100 in the abse nce of metabolic activation during a bacterial reverse mutation assay. There is little concern for the positive results as it was abolished by the presence of S9 and was not observed in the other tester strains specific for base

- pair changes. Based on the results of the genetic toxicology studies, it was concluded that there is no mutagenic concern for fluensulfone or the fluensulfone metabolites tested.

Testing in acute lethality studies with fluensulfone technical

- grade material resulted in low toxicity classifications via the oral (Toxicity Category III), dermal (Toxicity Category III), and inhalation (Toxicity Category IV) routes of exposure

. Fluensulfone technical

- grade material was not an irritant to eyes (Toxicity Category IV) or skin (Toxicity Categ ory IV) but was a skin sensitizer

. Similar results were obtained in acute lethality studies with a granular formulation ( Appendix A.2 ) ; however, the granular formulation was determined not to be a skin sensitizer.

Oral acute lethality studies were also co nducted with the metabolites MeS, BSA, or TSA, each at 2000 mg/kg bw

. By the oral route of exposure, MeS was of moderate toxicity (Toxicity Category II) and both BSA and TSA were of low toxicity (Toxicity Category III)

. HED notes that all animals treated w ith BSA or TSA survived the entire study period and that the toxicity category for those metabolites is based on the dosing level rather than on actual LD 50 

### estimates

. In 28

- day rat oral toxicity studies with BSA and TSA, no treatment

- related effects were observed at any dose (limit

- dose = 1000 mg/kg/day). Based on the available data addressing toxicity of the BSA and TSA metabolites, the Agency has determined that they are not of toxicological concern.

4.4 Safety Factor for Infants and Children (FQPA Safe ty Factor)

The toxicology and the exposure databases for fluensulfone support a reduction of the required 10X FQPA safety factor to 1X based on the following considerations: the completeness of the toxicity database including adequate studies to assess p otential susceptibility in the young; there is no indication of quantitative susceptibility in the developmental and reproductive toxicity studies, and there are no residual uncertainties concerning pre

- or post

- natal toxicity; the endpoints and doses cho sen for risk assessment are protective of the qualitative susceptibility observed in the 2

- generation reproduction study; acute and subchronic neurotoxicity studies (ACN and SCN) are available

. In addition, all endpoints used in the risk assessment are
pro tective of the potential neurotoxicity observed in the ACN, and a developmental neurotoxicity study is not required

. The dietary assessment is based on reliable data based on field trial (high end) residues and modeled drinking water residues, and will not underestimate exposure.

4.4.1 Completeness of the Toxicology Database

The toxicology database is considered complete and is adequate for the purpose of assessing pre

and postnatal susceptibility

. Acceptable/guideline developmental toxicity studies in rats and rabbits and a reproduction study in rats, as well as acute and subchronic neurotoxicity studies in rats are available for FQPA assessment

. A developmental neurotoxicity study is not required

.

### Fluensulfone D427486

Page 20 of 57 4.4.2 Evidence of Neurotoxicity

Decreased locomotor activity in females, and decreased spontaneous activity, decreased rearing, and impaired righting response in both sexes were observed in the acute neurotoxicity study at the lowest dose tested. However, no other evidence for neurotoxicity was observed in the other studies in the toxicity database, including a subchronic neurotoxicity study

. The doses and endpoints chosen for risk assessment are all protective of the effects seen in the acute neurotoxicity study

. For examp le, the NOAEL for acute dietary exposure (16 mg/kg/day) from the 2

- generation reproduction study is 6

- times lower than the dose at which effects were observed in the acute neurotoxicity study ( LOAEL = 100 mg/kg)

. A developmental neurotoxicity study is not required.

4.4.3 Evidence of Sensitivity/Susceptibility in the Developing or Young Animal

No evidence of quantitative or qualitative susceptibility was seen in developmental toxicity studies in rats and rabbits

. Fetal effects in those studies occurred in the presence of maternal toxicity and were not considered more severe than the maternal effects

. However, there was evidence of increased qualitative, but not quantitative, susceptibility of pups in the 2

- generation reproduction study in rats

. Maternal eff ects observed in that study were decreased body weight and body weight gain; at the same dose, effects in offspring were decreased pup weights, decreased spleen weight, and increased pup loss (PND 1

- 4).

Although there is evidence of increased qualitative susceptibility in the 2

- generation reproduction study in rats, there are no residual uncertainties with regard to pre

- and/or post

- natal toxicity following in utero exposure to rats or rabbits and pre

- and/or post

- natal exposures to rats

. Considering the o verall toxicity profile, the clear NOAEL for the pup effects observed in the 2

- generation reproduction study, and that the doses selected for risk assessment are protective of all effects in the toxicity database including the offspring effects , the degree of concern for the susceptibility is low.

4.4.4 Residual Uncertainty in the Exposure Database

There is no residual uncertainty in the exposure database

. The current dietary assessment is based on high

- end assumptions such as tolerance

- equivalent residu e levels of the parent compound in foods, 100% crop treated, and modeled estimates of residues in drinking water

. All of the exposure estimates are based on conservative assumptions and are not likely to underestimate risk.

4.5 Toxicity Endpoint and Point of Departure Selections

4.5.1 Dose

- Response Assessment

The toxicity endpoints and points of departure are presented in Table 4.5.4.1 and Table 4.5.4.2, and the details for selecting toxicity endpoints and points of departure for various exposure scenari os are presented in Appendix A.

### Fluensulfone D427486

Page 21 of 57 For fluensulfone, HED has selected endpoints from the available data to establish points of departure (PODs) for the risk assessment that are protective of the observed adverse effects across the entire database

.

For acute dietary exposure, two studies with effects after one or two doses are available at similar LOAELs: pup mortality in the 2

- generation reproduction toxicity study in rats (122 mg/kg/day) and decreased motor activity in the ACN in rats (100 mg/kg/day)

. The POD for acute dietary exposure was chosen from the 2

- generation reproductive toxicity study in rats

. In this study, an increase in pup loss between PND 1 and 4 in the F1 and F2 offspring was observed at 122.0/169.1 mg/kg/day (M/F) with a NOAEL of 16.2 /23.0 mg/kg/day (M/F)

. The majority of the pup deaths occurred on post

- natal day 2, although there were also a number that occurred on post

- natal day 1

. Therefore, the deaths may be attributable to a single dose

. Effects observed in the ACN in rats also su pport the POD for acute dietary risk assessment

. In this study, decreased motor activity in females and decreased spontaneous activity, decreased rearing, and impaired righting response in both sexes were observed at the lowest dose tested (100 mg/kg) on t he day of dosing only. The POD was chosen from the 2

- generation reproduction study over the ACN study with no NOAEL for the following reasons: 1) T he 2

- generation study had a clear NOAEL (16.2 mg/k g/day) for the effects observed, 2) The minimal nature of t he findings at 100 mg/kg/day is supported by the two acute LD 50 

### studies which also reported clinical signs of slight severity at doses of 300 mg/kg /day, 3) The shape of the dose

- response curve for the decrease in motor activity ( a decrease of 26% at 100 mg/kg/day, 42% at 400 mg/kg/day, and 58% at 1200 mg/kg/day ) supports that an effect is not expected at a dose an order of magnitude lower (i.e., ~ 10 mg/kg/day), and 4) E vidence of neurotoxicity was not seen in any other studies, including short

- term gavag e studies such as the developmental rat or rabbit studies. Taken together, effects from a single dose would not be expected to occur at a dose of 16.2 mg/kg/day and the NOAEL from the 2

- generation reproduction study is considered protective of the effects observed in the ACN.

The chronic rat study was chosen for the chronic dietary endpoint over the chronic dietary studies from others species because the primary effects of the chemical were observed in this study (hematological effects, decreased body weig ht, and lung effects following chronic exposure) and the NOAEL from this study was protective of the effects observed in the other chronic studies. While the LOAEL of the 90

- day and chronic dog studies were less than 2

- fold higher than the chronic rat NOAE L, this is to some extent a product of dose spacing. For example, when the NOAELs and LOAELs are adjusted based on 3⁄4 body weight scaling, the y are quite similar (Table 4.5.1.1). Furthermore, the effects observed in the dog studies were considered minimall y adverse; the decreases in body weight were barely 10% in most studies and did not get worse over the course of the study and the effects on hematological parameters indicated a mild hemolytic anemia that was well

- compensated for and not likely to alter t he function of an individual under normal conditions. Taken together, HED is confident that using the chronic rat study is not under protective. The POD for chronic dietary exposure was based on a NOAEL of 9.6 mg/kg/day with decreased body weight in males

, hematology and clinical chemistry changes, histopathological effects in the lung and esophagus at the LOAEL of 57.7 mg/kg/day

.

### Fluensulfone D427486

Page 22 of 57 Table 4.5.1.1

. Human Equivalent Doses (HED) based on 3⁄4 body weight scaling

.
Study Dose (mg/kg/day) Test Species Human Equivalent (1
NOAEL LOAEL NOAEL LOAEL Chronic rat MRID 4857476 5 9.6 57.7 2.1 17.2

90

- day dog MRID 48574755 1.6 17.1 0.9 10.0 Chronic dog MRID 48574756 3.1 16.0 1.8 10.0

1 3⁄4 body weight scaling was used to calculate a human equivalent dose (HED) using the following equation: [(animal body weight/human body weight)^0.25]*animal NOAEL or LOAEL. For humans, a default body weight of 70 kg was assumed. For rats and dogs, the average combined sex body weight at the beginning of the study was used.



### For incidental oral exposure to children, HED also chose the chronic rat study. Although this is a long

- term study, it is appropriate for short

- and intermediate

- term durations since the database indicates that the effects observed occurred following shorter t erm durations and there appeared to be no progression of toxicity with time based on the dog studies. While there did appear to be some progression in the hematological effects in the rat, the shorter term rat studies were not chosen because the chronic ra t study included the signature effects of the chemical as part of the LOAEL and was consistent with the choice of the chronic study for the short

- and intermediate

term dermal exposure endpoint, where the effects seen in the 28

- day and 90

- day study would n ot be appropriate for that endpoint (see below)

. Other potential studies considered for short

- term exposure scenarios included the 28/90

- day dog and 28/90

- day rat studies. In the case of the dog studies, there appeared to be no progression of toxicity betw een the 90

- day and 1

- year study in which both had very similar NOAELs and LOAELs based on similar effects (decreased body weight and hematological changes both appearing around week 6). The 28

- day dog study was not considered relevant for endpoint selectio n because of the low number of dogs used in the study (2 per sex) which reduced the confidence in the findings. The 90

- day or 1

- year dog studies were not chosen for a short

- term endpoint because, as discussed for the chronic dietary endpoint, 3⁄4 body weight scaling indicated that the NOAEL and LOAEL of the chronic rat study was very similar to the dog studies and protective of the effects while providing a slightly higher NOAEL. Furthermore, the effects observed in the dog in both the 90

- day and 1

- year study were considered minimally severe

. Taken together, the chronic rat study is protective of the effects in the dog.

For short

- and /or intermediate

- term residential/occupational exposure scenarios involving dermal exposure, HED did not cho o se the 28

- day dermal toxicity study in rats conducted with the technical material

. Although that study is of the appropriate route and duration, the results using the technical material do not appear to reflect the high dermal absorption of the emulsifiable
concentrate (480 EC) observed in the in vivo and in vitro dermal penetrations studies

. The dermal toxicity study shows minimal toxicity following exposure of 2000 mg/kg/day to technical

- grade fluensulfone, and has a NOAEL of 400 mg/kg/day

. At that NOAEL, the oral

- equi valent dose assuming 60% absorption (approximate rat in vivo value at 10 hours) is 240 mg/kg/day, which is approximately 6

- fold higher than the LOAELs from oral subchronic toxicity studies with rats

. Given the lack of toxic response in the dermal toxicity study, HED has concluded that it is not representative of potential systemic exposure to fluensulfone from the 480 EC formulation, to which exposure would actually occur. Therefore, HED chose the chronic rat study discussed

### Fluensulfone D427486

Page 23 of 57 above, with a 9.5% dermal absorp tion factor (see Section 4.2.1), to derive the point

- of

- departure

. The chronic rat study was considered appropriate for short

- and intermediate

- term exposure as described above for incidental oral exposure. In addition to the rationale provided above, the 28

- day rat and 90

- day rat studies were not considered appropriate for a dermal endpoint because the primary effects observed at the LOAEL in each study were either α

- 2

- microglobulin induced kidney effects that are not relevant for human risk assessment (28

- and 90

- day rat) or portal

- of

entry effects that would not be expected following dermal exposure (90

- day rat).

For short

- and /or intermediate

- term residential/occupational exposure scenarios involving inhalation exposure, the POD was chosen from the 90

- d ay inhalation toxicity study in rats

. In this study, decreased body weight, decreased thymus weight, and histopathological changes in the nasal cavity of males; prolong ed prothrombin time in females; and histopathological changes in the epiglottis in both sexes were observed at the lowest dose tested (0.04 mg/L)

. Since a NOAEL could not be identified in this study, an additional 10X uncertainty factor for the use of a LOAEL to extrapolate to a NOAEL was applied to short

- and intermediate

- term inhalation

res idential/occupational exposure scenarios

. The methods and dosimetry equations described in EPA’s reference concentration (RfC) guidance and OPP’s guidance on the application of the RfC methodology are suited for calculating human

- equivalent concentration s (HECs) based on the inhalation toxicity N OAEL for use in margin of exposure (MOE) calculations

. The regional

- deposited

- dose ratio (RDDR), which accounts for the particulate diameter (mass median aerodynamic diameter [MMAD] and geometric standard deviatio n [  g 

### ] of aerosols), can be used to estimate the different dose fractions deposited along the respiratory tract

. The RDDR is also based on interspecies differences in ventilation and respiratory

- tract surface areas

. Thus, the RDDR can be used to adjust an observed inhalation particulate exposure of an animal to the predicted inhalation exposure for a human

. For the 90

- day inhalation study with fluensulfone, an RDDR for the extrathoracic region (based on effects observed in the nasal cavity) wa s estimated at 0.143 based on the reported MMAD of 1.02 μm, standard deviation (  g 

### ) of 1.59, and the respiratory

- tract surface area of the rat relative to the human . The extrathoracic region was chosen for the RDDR calculation as it provides an HED which i s protective of both the portal

- of

- entry and systemic effects. See section A.3.6 in Appendix 3 for the calculation of the HECs

. The level of concern (LOC) for all exposure scenarios was 300, which includes interspecies (3X), intraspecies (10X), and LOAEL

- t o

- NOAEL (10X) extrapolations

. The interspecies factor was reduced from 10X to 3X due to the HEC calculation accounting for pharmacokinetic (not pharmacodynamic) interspecies differences.

Long

- term dermal and inhalation exposures are not expected; therefor e, endpoints and doses were not selected

.

4.5.2 Recommendation for Combining Routes of Exposures for Risk Assessment

When there are potential occupational and residential exposures to a pesticide, the risk assessment must address exposures from three ma jor sources (oral, dermal, and inhalation) and determine whether the individual exposures from these routes can be combined based on the same toxicological effects. For fluensulfone, incidental oral and dermal exposures can be

### Fluensulfone D427486

Page 24 of 57 combined since the risk asses sments are based on studies with the same toxicological effects. While a similar systemic effect was observed in the studies used for incidental oral, dermal, and inhalation scenarios (decreased body weight), the derivation of the HEC s used for inhalation risk assessment (Appendix A.3.6) show that assessing inhalation exposure based on the portal

- of

entry effects is protective of the systemic endpoints since the portal

- of

- entry HEC is 18x lower than the systemic HEC

. As a result, inhalation exposure should not be combined with either the dermal or the oral routes of exposure.

4.5.3 Cancer Classification and Risk Assessment Recommendation Report of the Cancer Assessment Review Committee, TXR No. 0056419, J. Rowland; K. Middleton, 7 May 2014


### The Cancer Assessment Review Committee (CARC) classified fluensulfone as “Suggestive Evidence of Carcinogenicity” based on an increased incidence of alveolar/bronchiolar adenomas and carcinomas in the lung of mid

- and high

- dose female mice in the oncogenic ity study

. Tumors were not observed in the rat chronic toxicity/carcinogenicity study in either sex or in male mice

. There was no evidence of genotoxicity

. Although the mouse study showed that fluensulfone was associated with alveolar/bronchiolar adenomas and carcinomas in the female, the EPA has determined that quantification of cancer risk using a non

- linear approach (i.e., RfD) for fluensulfone will adequately account for all chronic toxicity, including carcinogenicity, that could result from exposure to fluensulfone

. That conclusion is based on the following considerations: (1) the tumors occurred in only one sex in one species; (2) fluensulfone and its metabolites are not mutagenic; and (3) no carcinogenic response was seen in either sex in the rat.

4. 5.4 Summary of Points of Departure and Toxicity Endpoints Used in Human Risk Assessment

Table 4.5.4.1

. Summary of Toxicological Doses and Endpoints for use in Fluensulfone Dietary and Non

Occupational Human Health Risk Assessments. Exposure/ Scenario Point of

Departure Uncertainty/

FQPA Safety Factors RfD, PAD,

Level of Concern for Risk Assessment Study and Toxicological Effects

Acute Dietary (All Populations, including Infants and Children and Females 13

- 49 years of age) Offspring

NOAEL= 16.2 mg/kg/day UF A = 10x

UF H =10x FQPA SF= 1x Acute RfD =

0.16 mg/kg/day

aPAD = 0.16 mg/kg/day 2

- generation reproduction

– rat

Offspring LOAEL = 122.0 mg/kg/day based on an increase in pup loss between PND 1 and 4 in the F1 and F2 offspring with the majority of deaths occurring on day 2.

Chronic Dietary (All Populations) NOAEL = 9.6

mg/kg/day UF A = 10x

UF H =10x FQPA SF= 1x Chronic RfD =

0. 10 mg/kg/day

cPAD = 0. 10 mg/kg/day 2

- year toxicity/carcinogenicity

- rat

LOAEL = 57.7 mg/kg/day based on decreased body weight in males, and hematology changes, clinical chemistry changes and histopathological effects in the lung and esophagus of both sexes.

### Fluensulfone D427486

Page 25 of 57 Table 4.5.4.1

. Summary of Toxicological Doses and Endpoints for use in Fluensulfone Dietary and Non

Occupational Human Health Risk Assessments. Exposure/ Scenario Point of

Departure Uncertainty/

FQPA Safety Factors RfD, PAD,

Level of Concern for Risk Assessment Study and Toxicological Effects

Incidental Oral (Short

- term) NOAEL = 9.6

mg/kg/day (chronic dog) UF A = 10x

UF H =10x FQPA SF= 1x Residential

LOC for MOE = 100 2

- year toxicity/carcinogenicity

- rat

LOAEL = 57.7 mg/kg/day based on decreased body weight in males, and hematology changes, clinical chemistry changes and histopathological effects in the lung and esophagus of both sexes. Dermal Short

and /or Intermediate

Term (1

- 30 days and 1

- 6 months) NOAEL= 9.6

mg/kg/day

DAF = 9.5% UF A =10x

UF H =10x FQPA SF= 1x Residential

LOC for MOE = 100 2

- year toxicity/carcinogenicity

- rat

LOAEL = 57.7 mg/kg/day based on decreased body weight in males, and hematology changes, clinical chemistry changes and histopathological effects in the lung and esophagus of both sexes. Inhalation Short

- and /or Intermediate

Term (1

- 30 days and 1

- 6 months) NOAEL= not

established (<0.04 mg/L)

HED = 0.135 mg/kg/day

See section A.3. 6 in Appendix A for HEC and HED calculations UF A =3x

UF H =10x UF L =10x FQPA SF= 1x Residential

LOC for MOE = 300 90

- day inhalation toxicity

– rat

LOAEL = 0.04 mg/L (lowest dose tested) based on weight loss in males, prolonged prothrombin time in females, decreased thymus weight in males, histopathological changes in the epiglottis in both sexes, and histopathological changes in the nasal cavity of males

.

Cancer Classification: Suggestive evi dence of carcinogenicity in humans based on lung tumors in

female rats

. The RfD is protective of potential cancer effects

. Point of Departure (POD) = A data point or an estimated point that is derived from observed dose

- response data and used to mark the beginning of extrapolation to determine risk associated with lower environmentally relevant human
exposures

. NOAEL = no observed adverse effect level

. LOAEL = lowest observed adverse effect level

. UF = uncertainty factor

. UF A = extrapolation from anima l to human (interspecies)

. UF H = potential variation in sensitivity among members of the human population (intraspecies)

. UF L = use of a LOAEL to extrapolate a NOAEL

. FQPA SF = FQPA Safety Factor

. PAD = population adjusted dose (a = acute, c = chronic)

. Rf D = reference dose

. MOE = margin of exposure

. LOC = level of concern

. HEC = human

- equivalent concentration. HED = human

- equivalent dose.

### Fluensulfone D427486

Page 26 of 57 Table 4.5.4.2

. Summary of Toxicological Doses and Endpoints for use in Fluensulfone Occupational Human Health Risk As sessments. Exposure/ Scenario Point of Departure Uncertainty Factors Level of

Concern for Risk Assessment Study and Toxicological Effects

Dermal Short

and Intermediate

Term (1

- 30 days and 1

- 6 months) NOAEL= 9.6 mg/kg/day

DAF = 9.5% UF A =10x UF H =10x Occupational

LOC for MOE = 100 2

- year toxicity/carcinogenicity

- rat

LOAEL = 57.7 mg/kg/day based on decreased body weight in males, and hematology changes, clinical chemistry changes and histopathological effects in the lung and esophagus of both sexes

. I nhalation Short

- and Intermediate

Term (1

- 30 days and 1

- 6 months) NOAEL= not established

(<0.04 mg/L)

HED = 0.405 mg/kg/day

See section A.3.6 in Appendix 3 for HEC and HED calculations UF A =3x UF H =10x UF L =10x Occupational

LOC for MOE = 300 90

- day inhalation toxicity

– rat

LOAEL = 0.04 mg/L (lowest dose tested) based on weight loss in males, prolonged prothrombin time in females, decreased thymus weight in males, histopathological changes in the epiglottis in both sexes, and histopathological changes in the nasal cavity of males

. Cancer Classification: Suggestive evi dence of carcinogenicity in humans based on lung tumors in

female mice

. The RfD is protective of potential cancer effects. Point of Departure (POD) = A data point or an estimated point that is derived from observed dose

- response data and used to mark the beginning of extrapolation to determine risk associated with lower environmentally relevant human exposures

. NOAEL = no observed adverse effect level

. LOAEL = lowest observed adverse effect level

. UF = uncertainty factor

. UF A = extrapolation from animal t o human (interspecies)

. UF H = potential variation in sensitivity among members of the human population (intraspecies)

. UF L = use of a LOAEL to extrapolate a NOAEL

. MOE = margin of exposure

. LOC = level of concern

. DAF = dermal absorption factor . HEC = huma n

- equivalent concentration. HED = human

- equivalent dose.



### 5.0 Dietary Exposure and Risk Assessment

5.1 Residues of Concern Summary and Rationale

The residue of concern for dietary assessment is the parent compound, fluensulfone. Residues of the metabolites BSA and TSA occur at levels significantly greater than fluensulfone; however, these metabolites are considered non

- toxic at levels that may occur from the use of fluensulfone.

Table 5.1

. Metabolites and Degradates to be included in the Risk As sessment and Tolerance Expression

. Matrix Risk Assessment Tolerance Expression

Plants Primary Crop Fluensulfone BSA *

Rotational Crop Fluensulfone BSA *

Livestock Ruminant Not defined Not defined

Poultry Not defined Not defined Drinking Water Fluensulfone + deschloro

- fluensulfone + MeS * Not Applicable

* BSA refers to the butene sulfonic acid metabolite (3,4,4

- trifluoro

- but

- 3

- ene

- 1

- sulfonic acid; Company Code M

3627); MeS refers to the methyl sulfone metabolite (5

- chloro

- 2

- methyl sulfonyl thiazole; Company Code M

- 3626).

### Fluensulfone D427486

Page 27 of 57 5 .2 Food Residue Profile

Residues in foods following treatment with fluensulfone typically include the metabolites BSA and TSA at quantifiable levels. In most field trial results, residues of fluensulfone, per se , are below the limit of quantification (LOQ; 0.01 ppm). Exceptions to this are trials conducted with carrot, celery, head lettuce, and leaf lettuce. Due to the frequency of occurrence of residues, BSA and TSA are better markers for enforcement than the parent compound, and due to the high potential for year

- to

- year carryover of TSA, BSA was determined to be the most appropriate residue for the enforcement residue definition. Both BSA and TSA have v ery low mammalian toxicity and, therefore, have been excluded from quantitative consider ation in the dietary assessment for fluensulfone.

Label Amendments

The petitioner requested a reduction to 150 days in the rotational crop plant

- back restriction for crops not listed on either the EC or G labels. In evaluating the requested revision to the rotational crop plant

- back restrictions, HED relied on data from field rotational crop studies conducted in green bean, lettuce, radish, tomato, and wheat, with pla nt

- back intervals (PBIs) of 30, 60, 120, 180, 270, and 365 days. For all crop

- PBI combinations, residues of fluensulfone were <0.01
ppm ; however, r esidues of BSA persisted in many crops to 180 days or more, and in wheat commodities to at least 365 days. On that basis, HED concluded that the label should prohibit rotation to cereal grains and restrict plant

- back to 365 days for all other crops not listed on either the EC or G labels

. In addition to the change in PBI, the petitioner requested that the label for the EC formulation be amended to allow a maximum application rate of 3.5 lb a.i./A for cucurbit vegetables and fruiting vegetables. This was the rate that was originally requested for these crop groups and which was used in the field trials submitted to support those uses. As such the data are appropriate for establishing tolerances for residues at the requested use rate. As previously noted in Section 2, the request for the increased application rate was accompanied by a request to revise the residue definition for enforcement to be in terms of the BSA metabolite only (with no stoichiometric conversion to parent compound) in order to be harmonized with the definition established by Codex. Given the offsetting changes to the tolerance level (increase in residues of 1.4

- fold due to the rate change and a decrease in residues of 1.5

- fold due to the definition change) and the rounding classes used by the OECD MRL/tolerance calculation procedures, there is no resulting numerical change in the tolerance levels for these to crop groups relative to their currently established values.

5.3 Water Residue Profile

Estimates of fluensulfone residues of concern in drinking water were provided by the Environmental Fate and Effects Division (EFED) in a memo titled “Fluensulfone: Drinking Water Exposure Assessment for Proposed New Uses on Turfgrass” (J. Lin, D424167, 19 February 2015). The memorandum notes that the estimated drinking water concentrations (EDWCs) based on the use on turf are less than those derived from the use on cucurbit vegetables and fruiting vegetables. As the use patterns for the new crops are essentially ide ntical

### Fluensulfone D427486

Page 28 of 57 to that for cucurbit and fruiting vegetables, HED has used the cucurbit/fruiting vegetable based EDWCs provided by EFED ( Table 5.3; J. Lin, D411774, 1 August 2013 and J. Lin, D417634, 30 January 2013). The EDWCs for groundwater are greater than thos e for surface water and are used in the dietary assessment.

Table 5.3

. Fluensulfone Estimated Drinking Water Concentrations for Dietary Risk Assessment (D411774+D417634)

. Residue Source (Tier: Model) Use Rate, lb a.i./A/yr Acute

EDWC, μg/L Chronic

EDWC, μg/L Surface Water (Tier II: PRZM

- EXAMS; D411774; FL Cucumber scenario) 3.57 11.8 0.173

Ground water (Tier I: PRZM

- GW; D417634; WI Corn scenario) 3.57 77.6 52.5



### 5.4 Dietary Risk Assessment

Acute and chronic aggregate dietary ( food and drinking water ) exposure and risk assessments were conducted using the Dietary Exposure Evaluation Model software with the Food Commodity Intake Database (DEEM

- FCID) Version 3.16

, which uses 2003

- 2008 food consumption data from the U.S. Department of Agriculture’s Natio nal Health and Nutrition Examination Survey, What We Eat in America, (NHANES/WWEIA)

.

5.4.1 Description of Residue Data Used in Dietary Assessment

Parent fluensulfone occurs at residue levels well below those of BSA, the residue defined for the enforceme nt of tolerances. Since tolerances do not include fluensulfone itself, HED has used the OECD MRL calculation procedures to derive tolerance

- equivalent residue levels for fluensulfone. For foods where the level of fluensulfone is expected to be below the li mit of quantification (LOQ), 0.01 ppm, HED has assumed that residues occur at the LOQ. For foods with quantifiable levels of fluensulfone, HED has assumed that residues occur at the tolerance

equivalent level. In addition to the new uses requested for flue nsulfone, the dietary assessment also addresses the label amendments affecting the previously registered uses for the compound.

5.4.2 Percent Crop Treated Used in Dietary Assessment

HED has assumed that all crops with existing, pending, or requested uses of fluensulfone are treated (i.e., 100 percent crop treated).

5.4.3 Acute and Chronic Dietary Risk Assessment

Both the acute and chronic dietary risk assessments are screening

- level assessments based on tolerance

- equivalent residues and 100% crop treate d. Generally HED is concerned when risk estimates exceed 100% of the acute and/or chronic population

- adjusted dose (aPAD/cPAD). For fluensulfone, risk estimates are all well below that threshold (Table 5.4.3) and are not of concern. As the assessment is ba sed on screening

- level assumptions, actual risks from dietary exposure to fluensulfone are likely to be less than those provided in the estimates below.

### Fluensulfone D427486

Page 29 of 57 Table 5.4.3

. Summary of Acute and Chronic Dietary Exposure (Food and Drinking Water) and Risk Estimate s for Fluensulfone.

Population Subgroup Acute Dietary (95 th Percentile) Chronic Dietary
Dietary Exposure

, mg/kg/day % aPAD Dietary Exposure

, mg/kg/day % cPAD
General U.S. Population 0.00 4 809 3.0 0.0013 35 1.3 All Infants (<1 year old) 0.01 4794 9. 3 0.0039 21 3.9 Children 1

- 2 years old 0.00 8369 5.2 0.0022 83 2.3 Children 3

- 5 years old 0.00 6513 4. 1 0.001811 1.8 Children 6

- 12 years old 0.00 4649 2.9 0.001234 1.2 Youth 13

- 19 years old 0.00 377 4 2.4 0.000943 <1 Adults 20

- 49 years old 0.00 4564 2. 9 0.00127 9 1.3 Adults 50

- 99 years old 0.00 4165 2.6 0.001297 1.3 Females 13

- 49 years old 0.00 4601 2.9 0.0012 76 1.3 Bold entries are maximum exposure and risk estimates.



### 6.0 Residential (Non

- Occupational) Exposure/Risk Characterization

There are no residential exposure scenarios associated with the petitioned

- for uses of fluensulfone; however, HED has re

- evaluated the available dermal toxicity data and has established a new point of departure for th is exposure pathway. As a result, new r esidential risk estimates associated with the existing use on turf have been included in this risk assessment

. Residential exposure is expected to be short

- term in duration

. Intermediate

- term exposures are not likely because of the intermittent nature of applications by homeowners and the use directions (i.e., irrigat ion following applications in order to get the active ingredient into the root zone and soil )

.

6.1 Residential Handler Exposure

The label recommends the end

- use product to be applied by a li censed applicator

. Also, the label requires handlers to wear PPE (i.e., chemical

- resistant gloves)

. Therefore, a quantitative exposure/risk assessment was not developed for residential handlers as the product is not intended to be applied by homeowners.

6 .2 Post

- Application Exposure

All residential post

- application assessments assume exposures occur on the same day as
treatment. The child dermal and incidental oral routes of exposure have been combined as it is likely that they can occur simultaneously ba sed on the use pattern and because the toxicological effects across these routes of exposure are the same. The individual incidental oral scenarios (i.e., hand

- to

- mouth

, object

- to

- mouth , and soil ingestion ) are considered to be inter

- related

, and it is likely that they occur interspersed amongst each other across time. Combining these scenarios with the dermal ex posure scenario would be overly conservative because of the conservative nature of each individual assessment. Assessment of episodic ingestion of granules by children resulted in a n MOE of 40 (LOC=100). T he episodic oral ingestion of g r anules is listed only as a poisoning scenario

, and its likelihood is diminished because the label instructs users to irrigate

### Fluensulfone D427486

Page 30 of 57 ( i.e., “water

- in”) treated areas following applications in order to get the product into the root zone and soil.

Table 6.2. Residential Post

- application Non

- cancer Exposure and Risk Estimates for Fluensulfone.

Lifestage Post

- application Exposure Scenario Application Rate
, lb ai /A ( 1 Dose
,

mg/kg/day ( 2 MOEs ( 3 Combined Routes (X indicates included in Combined MOE) Combined

MOE (4 Use Site Route of Exposure

Adult Turf (High Contact

Activities) Dermal 1.8 0.00039 2 4 ,0 00 N/A
Turf (Mowing Turf) Dermal 1.8 0.0000072 1,300,000 N/A Turf (Golfing) Dermal 1.8 0.0000270 350,000 N/A
Youth 11 < 16 old years old Turf (Mowing Turf) Dermal 1.8 0.0000082 1,200,000 N/A

Turf (Golfing) Dermal 1.8 0.0000320 300,000 N/A Children 6 < 11 years old Turf (Golfing) Dermal 1.8 0.0000378 250,000 N/A

Child 1 < 2 years old Turf (High Contact

Activities) Dermal 1.8 0.0007695 12,000 X

11,000

Hand

- to

- Mouth 1.8 0.0000747 130,000 X Object

- to

- Mouth 1.8 0.0000046 2,100,000 Soil Ingestion 1.8 0.0000610 160,000 Episodic Granul e Ingestion 1.8 0.41 40

1. Based on proposed label ( EPA Reg. No

. 53883

- GLT ). 2. Dose (mg/kg/day) algorithms provided in 2012 Residential SOPs ( http://www2.epa.gov/pesticide

- science

- and

- assessing

- pesticide

risks/standard

- operating

- procedures

- residential

- pesticide ). 3. MOE = POD (mg/kg/day) ÷ Dose (mg/kg/day). POD = 9.6 mg/kg/day for dermal and short

- term incidental oral exposure, and 16.2 mg/kg/da y for episodic granule ingestion. 4. Combined MOE = 1 ÷ (1/dermal MOE) + (1/inhalation MOE) + (1/incidental oral MOE), where applicable.



### 6.3 Residential Risk Estimates for Use in Aggregate Assessment

Although dermal and inhalation exposures both resulted in similar clinical signs (e.g., decrease body weight), the inhalation endpoint selected for risk assessment is based on portal

- of

- entry effects since these effects resulted in lower Human Equivalent C oncentrations (HECs) than the HEC for systemic effects

. Therefore, the portal

- of

- entry HEC is protective of the systemic effects and the dermal and inhalation exposure estimates were not combined since the toxicological effects are different for these routes of exposure

. The child dermal and oral routes of exposure have been combined as it is likely that they can occur simultaneously based on the use pattern and because the toxicological effects across these routes of exposure are the same

.

Table 6. 3 reflects the residential risk estimates that are recommended for use in the aggregate assessment for fluensulfone.

 The recommended residential exposure for use in the adult aggregate assessment reflects dermal exposure only from post

- application exposure to outdoor turf/lawn applications (high contact activities)

.

 The recommended residential exposure for use in the children 1<2 years old aggregate assessment reflects dermal and hand

- to

- mouth exposures from post

- application exposure to outdoor turf/lawn ap plications (high contact activities).

### Fluensulfone D427486

Page 31 of 57 Table 6.3

. Recommendations for the Residential Exposures for the Fluensulfone Aggregate Assessment.
Lifestage Exposure Scenario Dose
, mg/kg/day ( 1 MOE ( 2
Dermal Inhalation Oral Total Dermal Inhalation Oral Total

Adult Turf (High Contact

Activities) 0.0 0039 N/A N/A 0.00039 24,000 N/A N/A 24,000

Child 1 < 2 years old Turf (High Contact

Activities) 0.00077 N/A 0. 0000747 0.0008447 12,000 N/A 130,000 11,000

1. Dose = the highest dose for each applicable lifestage of all residential scenarios assessed

. Total = dermal + inhalation + incidental oral (where applicable)

. Dermal adult dose is from the high contact activities scenario. Child (1<2 years old) dermal and hand

- to

- mouth doses are from the high contact activit ies scenario. Both scenarios are listed in Table 6.2

. 2. MOE = the MOEs associated with the highest residential doses

.


### 7.0 Non

- Occupational Bystander Post

- A pplication Inhalation Exposure and Risk Estimates

Volatilization of pesticides may be a source of post

- application inhalation exposure to individuals nearby pesticide applications

. The agency sought expert advice and input on issues related to volatilization of pesticides from its Federal Insecticide, Fungicide, and Rodenticide Act Scientific Advisory Panel (SAP) in December 2009, and received the SAP’s final report on March 2, 2010 ( http://www.regulations.gov/#!documentDetail;D=EPA

- HQ

- OPP

- 2009

- 0687

- 0037 )

. The agency has evaluated the SAP report and has developed a Volatilization Screening Tool and a s ubsequent Volatilization Screening Analysis ( http://www.regulations.gov/# ! docketDetail;D=EPA

- HQ

- OPP

- 2014

- 0219)

. During Registration Review, the agency will utilize this analysis to determine if data (i.e., flux studies, route

- specific inhalation toxicological studies) or further analysis is required for fluensulfone.

8.0 Non

- Occupational Spray Drift Exposure and Risk Estimates

Spray drift is a potential source of exposure to those nearby pesticide applications

. This is particularly the case with aerial application, but, to a lesser extent, spray drift can also be a potential source of exposure from the ground application methods employed for fluensulfone

. The agency has been working with the Spray Drift Task For ce (a task force composed of various registrants which was developed as a result of a Data Call

- In issued by EPA), EPA Regional Offices and State Lead Agencies for pesticide regulation and other parties to develop the best spray drift management practices (see the agency’s Spray Drift website for more information). 1 

### The agency has also developed a policy on how to appropriately consider spray drift as a potential source of exposure in risk assessments for pesticides

. The potential for spray drift will be quantitatively evaluated for each pesticide during the Registration Review process which ensures that all uses for that pesticide will be considered concurrently

. The approach is outlined in the revised (2012) Standard Operating Procedures f or Residential Risk Assessment (SOPs)

- Residential Exposure Assessment Standard Operating Procedures Addenda 1: Consideration of Spray Drift

. This document outlines the quantification of indirect non

- occupational exposure to drift

.

1 Available: http://www2.epa.gov/reducing

- pesticide

- drift

### Fluensulfone D427486

Page 32 of 57 9 .0 Aggregate Exposure/Risk Character ization

In accordance with the FQPA, HED must consider and aggregate (add) pesticide exposures and risks from dietary sources as well as other sources for which there is reliable information

. In an aggregate assessment, exposures from relevant sources are added together and compared to quantitative estimates of hazard (e.g., a NOAEL or PAD), or the risks themselves can be aggregated

. When aggregating exposures and risks from various sources, HED considers both the route and duration of exposure.

9 .1 Acute Aggregate Risk

For fluensulfone, acute aggregate risk estimates are equivalent to the acute dietary risk estimates (Section 5.4) and are not of concern.

9 .2 Short

- Term Aggregate Risk

In assessing short

- term aggregate risk, HED has used the residential exposure estimates provided in Table 6.3 in combination with the chronic dietary exposure estimates, as an estimate o f co

occurring dietary exposure, to derive short

- term aggregate exposure estimates.

Table 9 .2

. Fluensulfone Aggregate Risk Estimates.
Lifestage Exposure Estimate

, mg/kg/day ( 1 

### MOE ( 2 

### Dietary Dietary Residential Total Aggregate Adult 0.00128 8 7,500 24,000 5,700 Child 1 < 2 years old 0.002274 4,200 1 1 ,000 3,000

1 See Table 5.4.3.

2 Dietary MOE = 9.6 mg/kg/day ÷ Dietary E xposure ; Residential To tal MOE from Table 6.3; Aggregate = 1 ÷ (1/MOE Dietary + 1/MOE Residential Total )



### The residential exposure scenarios are for dermal and/or oral routes of exposure, for which the level of concern for MOEs is 100. The aggregate MOEs are greater than 100, indicating that short

- term aggregate risk estimates are not of concern.

9 .3 Intermediate

- Term Aggregate Risk

As previously noted, intermediate

- term residential exposures are not expected; therefore, intermediate

- term aggregate risk is not a con cern and quantitative estimates were not calculated.

9

. 4 Chronic Aggregate Risk

For fluensulfone, long

- term exposure from non

- dietary sources is not expected. Therefore chronic aggregate risk estimates are equivalent to the chronic dietary risk estimates (Section 5.4) and are not of concern.

### Fluensulfone D427486

Page 33 of 57 9

. 5 Cancer Aggregate Risk

Fluensulfone is classified as having “suggestive evidence of carcinogenicity in humans.” The RfD is considered to be protective of potential cancer effects. Based on the chronic aggregate/dietary risk estimates, cancer risk is not a concern for fluensulfone.

10 .0 Cumulative Exposure/Risk Characterization

Unlike other pesticides for which EPA has fo llowed a cumulative risk approach based on a common mechanism of toxicity, EPA has not made a common mechanism of toxicity finding as
to fluensulfone and any other substances and fluensulfone does not appear to produce a toxic metabolite produced by other substances. For the purposes of this tolerance action, therefore, EPA has not assumed that fluensulfone has a common mechanism of toxicity with other substances. For information regarding EPA’s efforts to determine which chemicals have a common mechanism o f toxicity and to evaluate the cumulative effects of such chemicals, see the policy statements released by EPA’s Office of Pesticide Programs concerning common mechanism determinations and procedures for cumulating effects from substances found to have

a c ommon mechanism on EPA’s website at http://www.epa.gov/pesticides/cumulative/.

11 .0 Occupational Exposure/Risk Characterization

This assessment addresses occupational exposures and risks associated with the petitioned

- for new uses of fluensulfone . In add ition, due to revisions to the toxicological points of departure, this assessment includes re

- evaluation of exposures and risks associated with the previously registered uses on cucurbit vegetables, fruiting vegetables, and turf.

11 .1 Short

- Term Handler R isk

HED derived occupational handler risk estimates for the granular formulation of fluensulfone for turf

, typical

- acreage crop ( root vegetables) and high

- acreage crop ( tuber ous and corm vegetables) scenarios (Table 11 .1.1) ; and for the EC formulation for typical

- acreage row crop scenarios , which include the cucurbit vegetable s and fruiting vegetable s from the previous registration as well as the new uses for this assessment (Table 11 .1.2).

Occupational Handler Exposure Data and Assumptions A series of assumptions and exposure factors served as the basis for completing the occupational handler risk assessments , obtained either from the proposed labels or from HED’s typical assumptions used for completing occupational exposure assessments, unless otherwis e noted

. Each assumption and factor is detailed below on an individual basis.

Application Rate : The maximum proposed application rates are 3.5 lb a.i./A (EC) and 3.6 lb a.i./A (G), as listed in Table 3.3

.
Unit Exposures : It is the policy of HED to use the best available data to assess handler exposure

. Sources of generic handler data, used as surrogate data in the absence of chemical

- specific data, include PHED 1.1, the Agricultural Handler’s Exposure Task Force ( AHETF ) database, the

### Fluensulfone D427486

Page 34 of 57 Outdoor Residential Exposure Task Force (ORETF) database, or other registrant

- submitted occupational exposure studi es. Some of these data are proprietary (e.g., AHETF data), and subject to the data p rotection provisions of FIFRA. The standard values recommended for use in
pr edicting handler exposure that are used in this assessment, known as “unit exposures”, are outlined in the “Occupational Pesticide Handler Unit Exposure Surrogate Reference Table 2 

### ”, which, along with additional information on HED policy on use of surrogate data, including descriptions of the various sources, can be found at the agency website 3



### .
Area Treated

- Ground Equipment : The inputs for area treated, except chemigation, were based on information in ExpoSAC Policy 9.1.

 80 acres for groundboom applications on typical acreage field crops; and

 200 acres and 80 acres for tractor

- drawn spreader applications on high and typical acreage field crops , respectively.

Area Treated

– Chemigation: The registrant

, ADAMA, has conducted a survey titled “A Sur vey Quantifying the Number of Acres Chemigated per Day using Drip Irrigation in U.S. Farms " to determine a representative estimate for acres chemigated per worker per day to refine the default HED assumption of 350 acres chemigated per day. HED has reviewe d the survey data, confirmed the results using the raw data

, and found it acceptable to refine the current input assumption of 350 acres treated per day for chemigation ( D429723, Z. Figueroa, 8 April 2016 ). HED recommends the risk assessment rely on the su rveyed distribution of the average number of acres chemigated per day. The distribution appeared to be skewed to the right ( asymmetrical

, i.e., fewer observations were reported towards the higher percentile values of the number of acres chemigated per day in the distribution ), indicating that the upper percentiles are conservative estimates of the central tendency of this distribution. A range of risk estimates using the upper

end of that distribution (e.g., 90 th 

### , 95 th 

### , 99 th 

### percentile) has been presented to give a useful perspective of the range of risk estimates based on the average acres treated with chemigation per day. The 90 th 

### , 95 th 

### , and 99 th 

### percentiles correspond to 100, 155, and 440 acres per day

, respectively. HED’s default value of 350 acres treated per day represent s approximately the 98.7 th 

### %tile of the average acres per day distribution.

B ased on the survey results , focusing on the chemigation use pattern for fluensulfone ( i.e., pre

plant/pre

- transplant spray i ncorporated into soil for the control of nematodes )

, HED believes that the 95 th 

### percentile average acreage treated with chemigation per day (i.e., 155 acres chemigated per day) serv e s as a reasonable estimate for risk assessment

. HED notes that this findin g is limited to the specific conditions of this compound (i.e., soil applied for nematode control) and risk assessment, and may not be applicable to other compounds or risk assessment scenarios.

Exposure Duration: HED classifies exposures from 1 to 30 days as short

- term and exposures from 30 days to s ix months as intermediate

- term. Exposure duration is determined by many factors , including the exposed population, the use site, the pest pressure triggering the use of the pesticide, and the cultural pract ices surrounding that use site. For most agricultural uses, it is reasonable to believe that occupational handlers will not apply the same chemical every day for

2 Available: http://www2.epa.gov/sites/ production/files/2015

- 09/documents/handler

- exposure

- table

- 2015.pdf
3 Available: http://www2.epa.gov/pesticide

- science

- and

- asses sing

- pesticide

- risks/occupational

- pesticide

- handler

exposure

- data

### Fluensulfone D427486

Page 35 of 57 more than a one

- month time frame; however, there may be a large agribusiness and/or commercial applicators who apply a product over a period of weeks (e.g., completing multiple applications for multiple clients within a region)

. Based on the proposed and registered use pattern (i.e., 1

- 2 application s per year depending on the
rate ) , short

- and intermediate

- term exposures are expected for occupational handlers. In addition, the label s suggest rotat ing the end

- use product with nematicides with a different mode of action

. Mitigation/Personal Protective Equipment : Estimates of dermal and inhalation exposure were calculated at baseline attire (i.e., long

- sleeved shirts, long pants, shoes plus socks) and for various levels of PPE (i.e., chemical

- resistant gloves, PF5 and PF 10 respirators ) as well as engineering con trols (closed loading)

. Results are presented for label specified PPE and additional PPE as needed to achieve MOEs above the LOC

. The fluensulfone product labels direct mixers, loaders, applicators and other handlers to wear chemical

- resistant gloves in ad dition to the baseline layer of clothing. The Nimitz ® 

### 15G label (EPA Reg. No. 66222

- EAE ) also specifies that operators of tractor

- drawn spreaders must wear a PF10 respirator

. Combining Exposures/Risk Estimates Although some of the toxicological effects for the dermal and inhalation exposure routes were similar (e.g., decrease body weigh t ), these exposure routes are not combined in this assessment because the inhalation POD is based on portal

- of

- entry effects.

Summary of Occupational Handler Non

- Cancer E xposure and Risk Estimates For both formulations, inhalation MOE s are below the level of concern of 300 for many scenarios. For the majority of those cases, addition of a PF5 respirator results in MOEs greater than 300 . For one scenario with the granular formulation (mixer/loader for tractor

- drawn spreader for high

- acreage crops), the addition of a PF10 respirator results in a n MOE of 270 ; engineering controls are needed to obtain an MOE greater than 300 for this scenario

.

Tab le 11 .1.1

. Fluensulfone Occupational Handler Non

- Cancer Exposure and Risk Estimates for Granular End

- Use Product s (66222

- EAE and 53883

- GLT ). ( 1

Exposure Scenario (Granular) Crop Max. Applic. Rate, (2 lb ai/A Area Treated, A (3 Dermal Inhalation Unit Exposure, μg/lb ai (4 [Level of PPE] Dose,

mg/kg/day (5 MOE (6 Unit Exposure,

μg/lb ai (4 [Level of PPE] Dose
,

mg/kg/day (7 MOE ( 8
Mixer/Loader Tractor

- drawn Spreader Golf Course 1.8 40 8.4 [Baseline] 0.00072 13,000 1.7 [Baseline] 0.00153 270

0.34 [PF5 Respirator] 0.00031 1,300

Sod (Typical Application) 1.8 80 8.4 [Baseline] 0.00118 6,700 1.7 [Baseline] 0.00306 130

0.34 [PF5 Respirator] 0.00061 670

Sod (Rescue Treatment) 3.6 80 8.4 [Baseline] 0.00287 3,300 1.7 [Baseline] 0.00613 70

0.34 [PF5 Respirator] 0.00122 340

Typical Acreage Field Crop 3.6 80 6.9 [ Single Layer + Gloves ] 0.00236 4,100 1.7 [ Baseline ] 0.00613 66

### Fluensulfone D427486

Page 36 of 57 Tab le 11 .1.1

. Fluensulfone Occupational Handler Non

- Cancer Exposure and Risk Estimates for Granular End

- Use Product s (66222

- EAE and 53883

- GLT ). ( 1

Exposure Scenario (Granular) Crop Max. Applic. Rate, (2 lb ai/A Area Treated, A (3 Dermal Inhalation Unit Exposure, μg/lb ai (4 [Level of PPE] Dose,

mg/kg/day (5 MOE (6 Unit Exposure,

μg/lb ai (4 [Level of PPE] Dose
,

mg/kg/day (7 MOE ( 8 0.34 [PF5 Respirator] 0.00122 330

8.6 [E ng. C trl. ] 0.00295 3,300 0.083 [EC] 0.000299 1,400

High Acreage Field Crop 3.6 200 6.9 [ Single Layer + Gloves ] 0.0059 1,600 1.7 [ Baseline ] 0.0153 27

0.34 [PF5 Respirator] 0.00306 130

0.17 [PF10 Respirator] 0.00153 270

8.6 [ Eng. Ctrl. ] 0.00735 1,300 0.083 [Eng. Ctrl.] 0.000748 540

Applicator Tractor

- drawn Spreader Golf Course 1.8 40 9.9 [Baseline] 0.00085 11,000 1.2 [Baseline] 0.00108 380

Sod (Typical Application) 1.8 80 9.9 [Baseline] 0.0017 5,600 1.2 [Baseline] 0.00216 190

0.24 [PF5 Respirator] 0.00043 950

Sod (Rescue Treatment) 3.6 80 9.9 [Baseline] 0.00338 2,800 1.2 [Baseline] 0.00433 100

0.24 [PF5 Respirator] 0.00086 470

Typical Acreage Field Crop 3.6 80 7.2 [ Single Layer + Gloves ] 0.00246 3,900 0.12 [PF10 Respirator] 0.000433 940

2 [ Eng. Ctrl. ] 0.000684 14,000 0.22 [Eng. Ctrl.] 0.000793 510

High Acreage Field Crop 3.6 80 7.2 [ Single Layer + Gloves ] 0.00615 1,600 0.12 [PF10 Respirator] 0.00108 380

2 [ Eng. Ctrl. ] 0.00171 5,600 0.22 [Eng. Ctrl.] 0.00198 210

Loader/Applicator Belly Grinder Landscaping,

Turf (lawns, athletic fields, parks) 1.8 1 10,000 [Baseline] 0.0214 450 62 [Baseline] 0.0014 290

12.4 [PF5 Respirator] 0.000279 1,500

Rotary Spreader Golf Course,

Landscaping, Turf (lawns, athletic fields, parks) 1.8 5 440 [Baseline] 0.0047 2,000 10 [Baseline] 0.00113 360

1 EPA Registration File Symbol for the end

- use product. 2 Based on registered or proposed label s. 3 Exposure Scien ce Advisory Council Policy #9.1 or survey for number of acres treated with chemigation (MRID No. 49700502 ). 4 Based on the “Occupational Pesticide Handler Unit Exposure Surrogate Reference Table” ( September 2015 ); Level of mitigation : Baseline, PPE (PF5 Respirator)

. 5 Dermal Dose = Dermal Unit Exposure ( μ g/lb ai) × Conversion Factor (0.001 mg/ μ g) × Application Rate (lb ai/acre) × Area Treated Daily (A /day) × DAF (%) ÷ BW (kg). 6 Dermal MOE = Dermal NOAEL (mg/kg/day) ÷ Dermal Dose (mg/kg/day). LOC=100. 7 Inhalation Dose = Inhalation Unit Exposure ( μ g/lb ai) × Conversion Factor (0.001 mg/ μ g) × Application Rate (lb ai/acre ) × Area Treated Daily (A /day) ÷ BW (kg). 8 Inhalation MOE = Inhalation NOAEL (mg/kg/day) ÷ Inhalation Dose (mg/kg/day). MOE=3 00.

### Fluensulfone D427486

Page 37 of 57 Table 11 .1.2. Occupational Handler Non

- Cancer Exposure and Risk Estimates for End

- Use Product Fluensulfone 480EC (66222

- 243). 1

Exposure Scenario ( EC ) Crop Max. Applic. Rate
, lb ai/A (2 Area

Treated

, A ( 3 Dermal Inhalation Unit Exposure

, μg/lb ai ( 4 [Level of PPE] Dose
,

mg/kg/day (5 MOE (6 Unit Exposure

,

μg/lb ai ( 4 [Level of PPE] Dose
,

mg/kg/day (7 MOE ( 8
Mixer/Loader Groundboom Typical

Acreage Field Crops 3.5 80 37.6 [Single Layer + Gloves] 0.0125 770 0.219 [Baseline] 0.000766 5 4 0

Chemigation Typical

Acreage Field Crops 3.5 440 37.6 [Single Layer + Gloves] 0.0688 140 0.219 [Baseline] 0.00421 9 7

0.0438 [PF5 Respirator] 0.000844 49 0

8.6 [Eng. Ctrl.] 0.0157 610 0.083 [Eng. Ctrl.] 0.0016 26 0

155 37.6 [Single Layer

+ Gloves] 0.0242 400 0.219 [Baseline] 0.00149 28 0

0.0438 [PF5 Respirator] 0.000298 1,400

8.6 [Eng. Ctrl.] 0.00555 1,700 0.083 [Eng. Ctrl.] 0.000563 73 0

100 37.6 [Single Layer + Gloves] 0.0157 610 0.219 [Baseline] 0.000959 43 0

8.6 [Eng. Ctrl.] 0.00357 2,700 0.083 [Eng. Ctrl.] 0.000364 1,100

Applicator Groundboom Typical

Acreage Field Crops 3.5 80 16.1 [Single Layer + Gloves] 0.00536 1,800 0. 34 [Baseline] 0.00119 340

1 EPA Registration Number for the end

- use product. 2 Based on registered or proposed label s. 3 Exposure Scien ce Advisory Council Policy #9.1 or survey for number of acres treated with chemigation (MRID No. 49700502 ; 100 A=90 th percentile, 155 A=95 th percentile, 440 A=99 th percentile ). 4 Based on the “Occupational Pesticide Handler Unit Exposure Surrogate Reference Table” ( September 2015 ); Level of mitigation : Baseline, PPE (PF5 Respirator)

. 5 Dermal Dose = Dermal Unit Exposure ( μ g/lb ai) × Conversion Factor (0.001 mg/ μ g) × Application Rate (lb ai/acre) × Area Treated Daily (A /day) × DAF (%) ÷ BW (kg). 6 Dermal MOE = Dermal NOAEL (mg/kg/day) ÷ Dermal Dose (mg/kg/day). LOC=100. 7 Inhalation Dose = Inhalation Unit Exposure ( μ g/lb ai) × Conversion Factor (0.001 mg/ μ g) × Application Rate (lb ai/acre ) × Area Tr eated Daily (A /day) ÷ BW (kg). 8 Inhalation MOE = Inhalation NOAEL (mg/kg/day) ÷ Inhalation Dose (mg/kg/day). MOE=300.



### 11 .2 Short

- Term Post

- Application Risk

HED has evaluated the occupational post

- application exposures to fluensulfone for the use on typical row crops (both new uses and previously registered uses) as well as the use on turf.

11 .2.1 Dermal Post

- A pplication Risk

Row Crops

. There is a low potential for occupational post

- application exposure associated with the use of pre

- plant/pre

- emerg ent nematicides because there are no hand labor activities typically associated with the production of crops that would require significant contact with treated soil

. Furthermore, no foliage will be present at time of application that could lead to exposur e via post

- application contact activities

.

### Fluensulfone D427486

Page 38 of 57 T here is a potential for workers to contact treated soil during mechanically assisted cucurbit and fruiting vegetables transplanting activities ; however, this event is likely to result in negligible exposures be cause transplanting activities involve moving starter plants onto a rotating wheel while riding upon an implement being moved across a field

. In such cases, there would be minimal contact with machinery, which may carry small amounts of treated soil, becau se of the possibility of mechanical injury

. Also, commercial cultivation is typically in tarped, raised beds with small planting holes punched in the tops of the raised beds

. Even though fluensulfone is stable under environmental conditions, the parent com pound has approximately a 10

- day half

life in field dissipation studies which decrease s the potential for occupational exposure to treated soil

. These con siderations for application of fluensulfone to cucurbit and fruiting vegetables support HED’s conclusi on that dermal post

- application exposure is negligible

, and therefore a quantitative dermal post

- application exposure assessment was not conducted.

Sod and Turf

. A summary of the post

- application dermal exposure and risk estimates from use of fluensulfone on treated sod/turf is provided in Table 11 .2.1

. Post

- application dermal exposure estimates reflect turf transferrable residues from Day 0 after treatment and resulted in MOEs greater than 100 and are not of concern

. Estimated exposure could be much lower (i.e., MOEs much higher) due to the label recommendation to irrigate turf immediately after application for most effective nematode control.

Table 11 .2. 1

. Occupational Short

- Term, Post

- A pplication

, Non

- Cancer , Dermal Exposure and Risk Estimates for Fluen sulfone from use on Sod and Turf

. Crop/Site Activities Transfer Coefficient

, cm 2 /hr TTR ( 1 Dermal Dose

, mg/kg/day ( 2 MOE ( 3

Sod Farm (Rescue Treatment) Maintenance, Harvesting, Slab Transplanting/Planting 6,700 0.0022 0.000127 24,000

Sod Farm/Turf (Typical Application) 0.0011 0.000064 49,000

Golf Course Maintenance (greens only) 2,500 0.0011 0.000024 130,000 Maintenance 3,700 0.0011 0.000035 88,000 1. Predicted TTR at initial concentration (t 0 ) = 0.0022 ug/cm 2 at 3.6 lb ai/A or 0.0011 ug/cm 2 at 1.8 lb ai/A from chemical

- specific study ( EPA MRID No. 49552503 ). 2. Daily Dermal Dose = [ TTR (μg/cm 2 ) × Transfer Coefficient × 0.001 mg/μg × 8 hrs/day × dermal absorption ( 9.5 %)]  BW ( 80 kg). 3. MOE = POD (mg/kg/day) / Daily Dermal Dose. LOC=100.


### Restricted Entry Interval

Fluensulfone is classified as Toxicity Category III via the dermal route and Toxicity Category IV for skin and eye irritation potential . The EC formulation is a skin sensitizer , however the granular formulation is not. Since a qu antitative dermal post

- application exposure assessment was not conducted, the REI specified on the registered label is based on the acute toxicity of fluensulfone

. Under 40 CFR 156.208 (c) (2) (iii), active ingredients classified as Acute III or IV for acu te dermal, eye irritation and primary skin irritation are assigned a 12

- hour REI

. Therefore, the [156 subpart K] Worker Protection Statement interim REI of 12 hours should be listed o n the proposed and registered labels in order to protect agricultural wor kers from post

- application exposures to fluensulfone.

### Fluensulfone D427486

Page 39 of 57 11 .2.2 Inhalation Post

- A pplication Risk

There are multiple potential sources of post

- application inhalation exposure to individuals performing post

- application activities in previously treated fields

. These potential sources include volatilization of pesticides and resuspension of dusts and/or particulates that contain pesticides

. The agency sought expert advice and input on issues related to volatilization of pesticides from its Federal Insecticide, Fungicide, and Rodenticide Act Scientific Advisory Panel (SAP) in December 2009, and received the SAP’s final report on March 2, 2010 ( http://www.regulations.gov/#!documentDetail;D=EPA

- HQ

- OPP

- 2009

- 0687

- 0037 )

. The agency has evaluated the SAP report and has developed a Volatilization Screening Tool and a subsequent Volatilization Screening Analysis ( http://www.regulations.gov/#!docketDetail;D=EPA

- HQ

- OPP

- 2014

- 0219 )

. During R egistration Review, the agency will utilize this analysis to determine if data (i.e., flux studies, route

- specific inhalation toxicological studies) or further analysis is required for fluensulfone.

In addition, the Agency is continuing to evaluate the av ailable post

- application inhalation exposure data generated by the Agricultural Reentry Task Force

. Given these two efforts, the Agency will continue to identify the need for and, subsequently, the way to incorporate occupational post

- application inhalatio n exposure into the agency's risk assessments.

1 2 .0 References

Cowins, J. 29 April 2016 . D 427502. Fluensulfone. Petition from ADAMA Agricultural Solutions, Ltd. (formerly Makhteshim Agan of North America, Inc.), and IR

- 4 for Registration of Uses on Crop Subgroup 1B, Crop Subgroup 1C, Crop Group 4, Crop Group 5, Crop Subgroup 13

- 07G, and Tobacco, Establishment of Associated Tolerances, and Label Amendments to Revise the Rotational Crop Plant

- Back Restriction and Increase the Application Rate for Crop Group s 8

- 10 and 9. Summary of Analytical Chemistry and Residue Data

. Cowins, J. 29 March 2016 . D 432134. Fluensulfone Acute and Chronic Aggregate Dietary (Food and Drinking Water) Exposure and Risk Assessments for the New Use Section 3 Registration Action on Ro ot Vegetables (Except Sugar Beet), Tuberous and Corm Vegetables, Leafy Vegetables (Except Brassica Vegetables), Brassica (Cole) Leafy Vegetables, Fruiting and Cucurbit Vegetables, and Low growing berry Crop Groups/Subgroups. Doherty, M., D’Agostino , J., and Figueroa, Z. 18 June 201 4 . D4 03767

. Fluensulfone: New Active Ingredient Human Health Risk Assessment of Proposed Uses on Cucurbit Vegetables and Fruiting Vegetables. Doherty, M., D’Agostino, J., and Figueroa, Z. 6 January 2015. D424168. Fluensul fone: Human Health Risk Assessment of the Proposed Use on Turf. Figueroa, Z. 12 April 2016 . D 43 2885

. Fluensulfone. Updated Occupational and Residential Exposure Assessment for the Uses on Golf Courses, Sports Fields, Commercial Areas, Sod Farms, and Resid ential Turfgrass/Lawns and Cucurbits and Fruiting Vegetables.

### Fluensulfone D427486

Page 40 of 57 Figueroa, Z. 12 April 2016. D 429723 . Fluensulfone. Review of the Study: “A Survey Quantifying the Number of Acres Chemigated per Day using Drip Irrigation in U.S. Farms” sponsored by Makhteshim Agan of North America D/B/A ADAMA. MRID No. 49700502. Lin, J. 1 August 2013. D411774. Fluensulfone: Drinking Water Exposure Assessment for Proposed New Registration for uses on cucurbits and fruiting vegetables. Lin, J. 20 January 2014. D417634. Fluensu lfone : Refined Drinking Water Exposure Assessment for Proposed New Registration for Uses on Cucurbits and Fruiting Vegetables Based on Ground Water Sources.
Lin, J. 20 October 2015. D428910. Fluensulfone: Drinking Water Exposure Assessment for Proposed Ne w Uses on Tuberous and Corm Subgroup 1C, Brassica (Crop Group 5A and 5B), Leafy Vegetables (Crop Group 4), Root Vegetables (Crop Group 1B), Strawberry including low growing berry subgroup (Crop Group 13

- 07G), and Tobacco
Thornton, G. 12 April 2016 . D 431914

. Fluensulfone. Occupational and Residential Exposure Assessment for a Proposed Use on Brassica subgroup 5A and 5B, Leafy vegetables group 4, Low growing berry subgroup 13

- 07G, Tobacco, Root vegetables 1B (including leafy portions), and Tuberous and corm vegetables 1C.

U.S.EPA. 1991. Alpha2u

- Globulin: Association with Chemically Induced Renal Toxicity and Neoplasia in the Male Rat . U.S. Environmental Protection Agency, Risk Assessment Forum, Washington, DC, EPA/625/3

- 91/019F (NTIS PB92143668), 1991.

### Fluensulfone D427486

Page 41 of 57 Attachment 1. Fluensulfone bibliography to support label amendments and new uses

.

MRID Study Author Title 49553604 Everich, R. Fluensulfone: Waiver Request for Residue Chemistry Guideline OPPTS 860.1480 Meat/Milk/Poultry/Eggs 49553607 Polakoff, B. Fluensulfone: Fulfillment of the Residue Data Requirements in Support of Tobacco Use 49553608 Jones, G

. Magnitude of the Residue of MCW

- 2 in Strawberries 49553609 Jones, G. Magnitude of the Residue of MCW

- 2 in Tobacco 49553610 Jones, G. Magnitude of the Residue of MCW

- 2 in Radish 49553611 Jones, G. Magnitude of the Residue of MCW

- 2 in Japanese Leafy Vegetables 49553612 Jones, G. Magnitude of the Residue of MCW

- 2 in Japanese Root Vegetables 49553613 Lennon, G. Magnitude of the Residue on Carrot 49553614 Jones, G. Magnitude of the Residue of MCW

- 2 in Brassica Vegetables 49553618 Jones, G. Magnitude of the Residue of MCW

- 2 in Leafy Vegetables 49643601 Lennon, G. Fluensulfone: Magnitude of the Residue on Potato 49709701 Jones, G. Magnitude of the Residue of Fluensulfone and Its Metabolites in Rotational Crops under Field Conditions 49552503 Riley, M. Determination of Transferable Residues of Fluensulfone on Turf Treated with MCW

- 2 1.5% GR Nematicide 49700502 Thompson, R. A Survey Quantifying the Number of Acres Chemigated per Day Using Drip Irrigation in U.S. Farms

### Fluensulfone D427486

Page 42 of 57 A ppendix A

. Toxicology Profile and Executive Summaries

A.1 Toxicology Data Requirements The requirements (40 CFR 158.340) for fluensulfone are below . Use of the new guideline numbers does not imply that the new (1998) guideline protocols were used.

Test Technical Fluensulfone Required Satisfied 870.1100 Acute Oral Toxicity 870.1200 Acute Dermal Toxicity 870.1300 Acute Inhalation Toxicity 870.2400 Primary Eye Irritation 870.2500 Primary Dermal Irritation 870.2600 Dermal Sensitization yes yes yes yes yes yes yes

yes yes yes yes yes 870.3100 Oral Subchronic (rodent) 870.3150 Oral Subchronic (nonrodent) 870.3200 21/28

- Day Dermal 870.3250 90

- Day Dermal 870.3465 90

- Day Inhalation yes yes yes

no yes yes

yes yes

- yes 870.3700a Developmental Toxicity (rodent) 870.3700b Developmental Toxicity (nonrodent) 870.3800 Reproduction yes yes yes yes

yes yes 870.4100a Chronic Toxicity (rodent) 870.4100b Chronic Toxicity (nonrodent) 870.4200a Oncogenicity (rat) 870.4200b Oncogenicity (mouse) 870.4300 Chronic/Oncogenicity yes yes yes yes yes yes

yes yes yes yes 870.5100 Mutagenicity

— Gene Mutation

- bacterial 870.5300 Mutagenicity

— Gene Mutation

- mammalian 870.5375 Mutagenicity

— Structural Chromosomal Aberrations 870.5550 Mutagenicity

— Other Genotoxic Effects yes yes yes yes yes

yes yes yes 870.6100a Acute Delayed Neurotoxicity (hen) 870.6100b 90

- Day Neurotoxicity (hen) 870.6200a Acute Neurotoxicity Screening Battery (rat) 870.6200b 90

- Day Neurotoxicity Screening Battery (rat) 870.6300 Developmental Neurotoxicity no

no yes yes

no --

-- yes yes

-- 870.7485 General Metabolism 870.7600 Dermal Penetration 870.7800 Immunotoxicity yes yes yes ye s

yes yes

### Fluensulfone D427486

Page 43 of 57 A.2 Toxicity Profile s

Table A.2.1

. Acute Toxicity Profile

- Fluensulfone technical
Guideline No. Study Type MRID(s) Results Toxicity Category 870.1100 Acute oral

- rat 48574745 LD 50 = 671 III 870.1100 Acute oral

- rat 48574746 LD 50 > 300 mg/kg but < 2000 mg/kg III

870.1200 Acute dermal

- rat 48575035 LD 50 > 2000 mg/kg III 870.1300 Acute inhalation

- rat 48574748 LC 50 > 5.1 mg/L IV 870.2400 Acute eye irritation

- rabbit 48574750 Non

- irritant IV 870.2500 Acute dermal irritation

- rabbit 48574749 Non

- irritant IV 870.2600 Skin sensitization

- guinea pig 48574751 Sensitizer N/A



### Table A.2.2

. Acute Toxicity Profile

- Fluensulfone granular formulations

Guideline No. Study Type MRID(s) Results (from study report) Toxicity Category

870.1100 Acute oral

– rat, 15GR 49488603 LD 50 > 2000 mg/kg III 870.1100 Acute oral

– rat, 1.5GR 49488608 LD 50 > 2000 mg/kg III 870.1200 Acute dermal

– rat, 15GR 49488604 LD 50 > 2000 mg/kg III 870.1300 Acute inhalation

- rat waived

- - 870.2400 Acute eye irritation

– rabbit, 15GR 49488605 Non

- irritant IV 870.2500 Acute dermal irritation

– rabbit,

15GR 49488606 Slightly irritating IV

870.2600 Skin sensitization

– mice, 15GR 49488607 Not a sensitizer N/A



### Table A.2.3

. Acute Oral Toxicity Profile

- Fluensulfone Metabolites
Metabolite Study Type MRID(s) Results Toxicity Category TSA Acute oral

- rat 48574783 LD 50 > 2000 mg/kg III MeS Acute oral

- rat 48574787 LD 50 > 300 mg/kg but < 2000 mg/kg II

BSA Acute oral

- rat 48574792 LC 50 > 2000 mg/kg III



### Table A.2.4

. Toxicity Profile

- Fluensulfone
Guideline Study Type Doses Tested/Study Classification MRID Results

870.3100 2003

- 90

- day

dietary

- rat mg/kg/day =

M: 0, 4.3, 8.3, 34.9, 139.0 F: 0, 4.8, 11.7, 53.1, 148.7

Acceptable/Guideline 48575035 NOAEL (mg/kg/day): M=8.3, F=11.7 LOAEL (mg/kg/day): M=34.9, F=53.1 based on kidney effects, observations in the pharynx and forestomach, increased cholesterol in females, and decreased body weight and body weight gain in males.

870.3100 2002

- 28

- day

dietary

- rat mg/kg/day=

M: 0, 10.4, 42.5, 152.0 F: 0, 12.2, 37.2, 165.9

Acceptable/Guideline 48575023 NOAEL (mg/kg/day): M=10.4, F=12.2 LOAEL (mg/kg/day): M=42.5, F=37.2 based on decreased body weight gain in both sexes, increased WBC in females, increased cholesterol in males

### Fluensulfone D427486

Page 44 of 57 Table A.2.4

. Toxicity Profile

- Fluensulfone
Guideline Study Type Doses Tested/Study Classification MRID Results

and renal pa thology in males. 870.3100 2003

- 90

- day

dietary

- mouse mg/kg/day =

M: 0, 11, 51, 228 F: 0, 18, 68, 252

Acceptable/Guideline 48574753 NOAEL (mg/kg/day): M=11, F=18 LOAEL (mg/kg/day): M=51, F=68 based on increased bilirubin, hematology effects in males, and reduced food consumption in females. 870.3100 2003

- 28

- day

dietary

- mouse mg/kg/day =

M: 0, 30, 101, 375 F: 0, 41, 155, 353

Acceptable/Guideline 48575024 NOAEL (mg/kg/day): M=30, F=41 LOAEL (mg/kg/day): M=101, F=155 based on decreased food consumption, decreased platelets in males, decreased absolute heart weight in males, and increased relative liver weight in females. 870.3150 2002

- 90

- day

dietary

- dog mg/kg/day =

M: 0, 0.2, 1.6, 17.1 F: 0, 0.2, 1.8, 18.0

Acceptable/Guideline 48574755 NOAEL (mg/kg/day): M=1.6, F= 1.8 LOAEL (mg/kg/day): M=17.1, F=18.0 based on decreased plasma and liver ALAT, liver effects, hematological findings, altered clinical chemistry, increased TSH, decreased body weight gains and decreased body weight in female s. 870.3150 2002

- 28

- day

dietary

- dog mg/kg/day =

M: 0, 1.9, 7.3, 31 F: 0, 2.0, 7.9, 30

Acceptable/Guideline 48574752 NOAEL (mg/kg/day): M=7.3, F= 7.9 LOAEL (mg/kg/day): M=31, F=30 based on slight decreases in body weight and slight increases in liver and thyroid weight. 870.3200 2011

- 28

- day

dermal

- rat mg/kg/day =

0, 80, 400, 2000

Acceptable/Guideline 48574758 Systemic: NOAEL (mg/kg/day): 400 LOAEL (mg/kg/day): 2000 based reduced body weight gain, increased prothrombin time and increased relative spleen weight in males; increased reticulocytes and increased cholesterol in females.

870.3465 2012

- 90

- day

inhalation

- rat mg/L/day =

0, 0.04, 0.2, 1.0

Acceptable/Guideline 48575045 NOAEL (mg/L/day): Not determined LOAEL (mg/kg/day): 0.04 based on weight loss in males, prolonged prothrombin time in females, decreased thymus weight in males, histopathological changes in the epiglottis in both sexes, and histopathological changes in the nasal cavity of males. 870.3700 2003

-

developmental
tox

- rat mg/kg/day =

0, 8, 50, 300

Acceptable/Guideline 48574771 Maternal : NOAEL (mg/kg/day): 50 LOAEL (mg/kg/day): 300 based on decreased body weight and food consumption.

### Fluensulfone D427486

Page 45 of 57 Table A.2.4

. Toxicity Profile

- Fluensulfone
Guideline Study Type Doses Tested/Study Classification MRID Results

Developmental : NOAEL (mg/kg/day): 50 LOAEL (mg/kg/day): 300 based on decreased body weight. 870.3700 2009

-

developmental
tox

- rabbit mg/kg/day =

0, 2.5, 10, 40

Acceptable/Guideline 48574770 Maternal : NOAEL (mg/kg/day): 10 LOAEL (mg/kg/day): 40 based on transient weight loss and decreased food consumption, GD6

- 9.

Supported by significant toxicity at 50 mg/kg/day (marked body weight loss, cold ears, decreased food intake, and discolored urine) observed in the range finding study.

Developmental : NOAEL (mg/kg/day): 10 LOAEL (mg/kg/day): 40 based on reduced body weight and incompl ete ossification of digit 5 of the medial phalanx in both forelimbs. 870.3800 2011

- 2

-

generation reproduction

rat mg/kg/day =

P, male: 0,1.9, 15.4, 114.2, P, female: 0, 2.7, 22.8, 164.8 F1, male: 0, 2.0, 17.0, 129.7 F1, female: 0, 2.9, 23.3, 169.1

Acceptable/Guideline 48574769 Parental : NOAEL (mg/kg/day): M=16.2, F=23.0 LOAEL (mg/kg/day): M=122.0, F=169.1 based on decreased body weight

Reproductive : NOAEL (mg/kg/day): M=16.2, F=23.0 LOAEL (mg/kg/day): M=122.0, F=169.1 based on an increase in post

- natal pup loss in both P and F1 generations.

Offspring : NOAEL (mg/kg/day): M=16.2, F=23.0 LOAEL (mg/kg/day): M=122.0, F=169.1 based on decreased pup and spleen weights. 870.4100 2011

- 1

- year

dietary

- dog mg/kg/day =

M: 0, 0.1, 1.5, 3.1, 16.0 F: 0, 0.1, 1.5, 3.3, 16.2

Acceptable/Guideline 48574756 NOAEL (mg/kg/day): M=3.1, F= 3.3 LOAEL (mg/kg/day): M=16.0, F=16.2 M: based on decreased body weight and changes in hematological and clinical chemistry parameters in both sexes. 870.4200 2011

- 18

- month

carcinogenicity

- mouse mg/kg/day =

M: 0, 4.2, 27.6, 152.3 F: 0, 6.4, 39.0, 188.4

Acceptable/Guideline 48574766 NOAEL (mg/kg/day): M=4.2, F=6.4 LOAEL (mg/kg/day): M=27.6, F=39.0 based on an increased incidence of lung bronchiolization and decreased body weight and body weight gain in males. Increased incidence of lung adenomas

### Fluensulfone D427486

Page 46 of 57 Table A.2.4

. Toxicity Profile

- Fluensulfone
Guideline Study Type Doses Tested/Study Classification MRID Results

above historical controls was observed in females; combined adenoma/carcinomas was also increased (carcinoma only increased trend). 870.4300 2011

- 2

- year

toxicity/carcino genicity

- rat mg/kg/day =

Oncogenicity group M: 0, 1.4, 9.6, 57.7 F: 0, 1.7, 11.6, 69.3

Chronic toxicity group M: 0, 1.6, 11.0, 66.3 F: 0, 1.9, 13.1, 75.2

Acceptable/Guideline 48574765 NOAEL (mg/kg/day): M=9.6, F= 11.6 LOAEL (mg/kg/day ): M= 57.7 , F= 69.3 based on decreased body weight in males

, and hematology and clinical chemistry findings and histopathological changes in the lungs and esophagus in both sexes.

870.5100 2002

- Bacterial

reverse mutation assay (MCW

- 2) Test 1: 0, 16, 50, 158, 500,

1581, or 5000  g/plate ( Salmonella typhimurium ) in the presence and absence of metabolic activation ( + S9). Test 2: 0, 1000, 2000, 3000, 4000, 5000, or 6000
 g/plate ( Salmonella typhimurium ) in the presence and absence of metabolic activation ( + S9). Test 3: 0, 375, 750, 1300, 2600, or 5200  g/plate ( Salmonella typhimurium ) in the absence of metabolic activation (

- S9).

Acceptable/Guideline 48574759/ 48575015 Negative with strains TA1535, TA1537,

TA98, and TA102.

Weakly positive with strain TA 100.

870.5100 2008

- Bacterial

reverse mutation assay (MCW

- 2) Test 1: 0, 3, 10, 33, 100,

333, 1000, 2500, or 5000
 g/plate ( Salmonella typhimurium

- Escherichia coli ) in the presence and absence of metabolic activation ( + S9). Test 2: 0, 33, 100, 333, 1000, 2500, or 5000
 g/plate ( Salmonella typhimurium

- Escherichia coli ) in the presence and absence of metabolic activation ( + S9). 48574760 Negative

### Fluensulfone D427486

Page 47 of 57 Table A.2.4

. Toxicity Profile

- Fluensulfone
Guideline Study Type Doses Tested/Study Classification MRID Results

Acceptable/Guideline 870.5100 2011

- Bacterial

reverse mutation assay (MCW

- 2) Test 1: 0, 10, 32, 100, 316,

1000, 2500, or 5000
 g/plate ( Salmonella typhimurium

- Escherichia coli ) in the presence and absence of metabolic activation ( + S9). Test 2: 0, 3, 10, 32, 100, 316, 1000, 2500, or 5000
 g/plate ( Salmonella typhimurium

- Escherichia coli ) in the presence and ab sence of metabolic activation ( + S9).

Acceptable/Guideline 48574761 Negative

870.5100 2010

- Bacterial

reverse mutation assay (MCW

- 2 metabolite #3625) Test 1: 0, 3, 10, 33, 100,

333, 1000, 2500, or 5000
 g/plate ( Salmonella typhimurium

- Escherichia coli ) in the presence and absence of metabolic activation ( + S9). Test 2: 0, 33, 100, 333, 1000, 2500, or 5000
 g/plate ( Salmonella typhimurium

- Escherichia coli ) in the presence and absence of metabolic activation ( + S9).

Acceptable/Guideline 48574784 Negative

870.5100 2010

- Bacterial

reverse mutation assay (MCW

- 2 metabolite #3626) Test 1: 0, 3, 10, 33, 100,

333, 1000, 2500, or 5000
 g/plate ( Salmonella typhimurium

- Escherichia coli ) in the presence and absence of metabolic activation ( + S9). Test 2: 0, 33, 100, 333, 1000, 2500, or 5000
 g/plate ( Salmonella typhimurium

- Escherichia coli ) in the presence and absence of metabolic activation ( + S9). Test 3: 0, 100, 333, 1000, 2500, 3750, or 5000
 g/plate ( Salmonella typhimurium

- Escherichia coli ) in the presence a nd 48574788 Negative, except positive with Salmonella typhimurium strain TA100 in the absence of metabolic activation

### Fluensulfone D427486

Page 48 of 57 Table A.2.4

. Toxicity Profile

- Fluensulfone
Guideline Study Type Doses Tested/Study Classification MRID Results

absence of metabolic activation ( + S9).

Acceptable/Guideline 870.5100 2010

- Bacterial

reverse mutation assay (MCW

- 2 metabolite #3627) Test 1: 0, 3, 10, 33, 100,

333, 1000, 2500, or 5000
 g/plate ( Salmonella typhimurium

- Escherichia coli ) in the presence and absence of metabolic activation ( + S9). Test 2: 0, 33, 100, 333, 1000, 2500, or 5000
 g/plate ( Salmonella typhimurium

- Escherichia col i ) in the presence and absence of metabolic activation ( + S9).

Acceptable/Guideline 48574793 Negative

870.5300 2003

- In vitro

mammalian cell gene mutation assay (MCW

- 2) Without activation: 0, 24,

32, 40, 48, 56, 64, 72
 g/ml With activation: 0, 20, 30, 40, 50, 60, 70, 80  g/ml

Acceptable/Guideline 48574763 Negative

870.5300 2011

- In vitro

mammalian cell gene mutation assay (MCW

- 2 metabolite #3626) Without activation: test1 =

0, 3.8, 7.5, 15, 30, 40, 50, 60  g/ml , test 2 = 0, 5.5, 10.9, 21.9, 43.8, 87.5, 131.3, 175  g/ml

With activation: test 1 = 0, 37.5, 75, 150, 300, 600, 800, 1000  g/ml, test 2 = 0, 87.5, 175, 350, 700, 800, 900, 1000  g/ml

Acceptable/Guideline 48574789 Negative

870.5375 2010

- In vitro

mammalian cell chromosome aberration test (MCW

- 2) 0, 62.5, 125, 250, 500,

1000 μg/mL with and without metabolic activation

Acceptable/Guideline 48574762 Negative

870.5375 2010

- In vitro

mammalian cell chromosome aberration test (MCW

- 2 Test 1: 0, 9.3, 18.5, 37,

74.1, 148.1, 296.3, 592.5, 1185, 2370 μg/mL with and without metabolic activation 48574785 Negative

### Fluensulfone D427486

Page 49 of 57 Table A.2.4

. Toxicity Profile

- Fluensulfone
Guideline Study Type Doses Tested/Study Classification MRID Results

metabolite #3625) Test 2: 0, 9.3, 18.5, 37,

74.1, 148.1, 296.3, 592.5, 1185, 2370 μg/mL without metabolic activation and 148.1, 296.3, 592.5, 1185, 2370 μg/mL with metabolic activation

Acceptable/Guideline 870.5375 2010

- In vitro

mammalian cell chromosome aberration test (MCW

- 2 metabolite #3627) Test 1: 0, 8.3, 16.6, 33.3,

66.6, 133.2, 266.4, 532.8, 1065.5, 2131 μg/mL with and without metabolic activation

Test 2: 0, 8.3, 16.6, 33.3, 66.6, 133.2, 266.4, 532.8, 1065.5, 2131 μg/mL without metabolic activation and 133.2, 266.4, 532.8, 1065.5, 2131
μ g/mL with metabolic activation

Acceptable/Guideline 48574794 Negative

870.5395 2003

-

mammalian erythrocyte micronucleus test (MCW

- 2) mg/kg/day = 0, 75, 150,

300

Acceptable/Guideline 48574764 Negative

870.5395 2011

-

mammalian erythrocyte micronucleus test (MCW

- 2 metabolite #3625) mg/kg/day = 0, 500,

1000, 2000

Acceptable/Guideline 48574786 Negative

870.5395 2011

-

mammalian erythrocyte micronucleus test (MCW

- 2 metabolite #3626) mg/kg/day = 0, 125, 250,

500

Acceptable/Guideline 48574791 Negative

870.5395 2010

-

mammalian erythrocyte micronucleus test (MCW

- 2 metabolite #3627) mg/kg/day = 0, 500,

1000, 2000

Acceptable/Guideline 48574795 Negative

### Fluensulfone D427486

Page 50 of 57 Table A.2.4

. Toxicity Profile

- Fluensulfone
Guideline Study Type Doses Tested/Study Classification MRID Results

870.5550 2011

-

unscheduled DNA synthesis (MCW

- 2 metabolite #3626) mg/kg/day = 0, 250, 500

Acceptable/Guideline 48574790 Negative

870.6200 2010

- Acute

neurotoxicity

rat mg/kg/day = 0, 100, 400,

1200

Acceptable/Guideline 48574773 NOAEL (mg/kg/day): not identified LOAEL (mg/kg/day): 100 based on decreased spontaneous activity, decreased rearing, impaired righting response, and reduced locomotor activity in females. 870.6200 2011

- 90

- day

neurotoxicity

rat mg/kg/day =

M: 0, 6, 31, 153 F: 0, 7, 34, 162

Acceptable/Guideline 48574774 NOAEL (mg/kg/day): M=31, F=34 LOAEL (mg/kg/day): M=153, F=162 based on decreased food consumption, decreased body weight gain, and decreased body weight in males. 870.7485 2011

-

Metabolism and excretion, single oral

- rat ( [ thiazole

14 C] MCW

- 2 and [ butene

14 C] MCW

- 2 ) mg/kg/day =

5 and 500

Acceptable/Guideline 48574742 The recovery of radioactivity was 91.3

- 97.3% of the administered dose for all groups of rats

. The disposition and excretion of radiolabel for males and females were generally similar

. Urine was the major route of excretion for both radiolabel posi tions; 75

- 88% of the administered dose was excreted in urine depending on the dosing

. Unmetabolized fluensulfone was not detected as a significant residue in either urine or feces

. The study investigators indicated that initially the parent compound probab ly reacts with glutathione to displace butene sulfinic acid, the major urinary metabolite

. 870.7485 2011

-

Metabolism and excretion, repeat oral

- rat ( [ butene

14 C] MCW

- 2 ) mg/kg/day =

5

Acceptable/Guideline 48574744 The recovery of excreted radiolabel was 94

- 99% for individual rats

. Radiolabel was found mainly in urine (71

- 83%), feces (9

- 11%) and the cage wash (6

- 16%)

. One day after dosing with radiolabeled fluensulfone, an average of 0.6

- 0.8% of the administered radiolabel was in liver and 0.1% in kidn ey with 1.7

- 2.1% in the carcass (selected tissues removed) and 4.5

- 4.7% remained in the gastro

- intestinal tract

. By 7 days after treatment with radiolabeled fluensulfone, an average of 0.1

- 0.2% of the administered radiolabel remained in liver and 0.03% in kidney. There were no significant sex differences in either elimination or tissue residues

. Analysis of urine showed four major metabolites identified as thiazole sulfonic acid (TSA), glucuronide I, glucuronide II and thiazole mercapturate. 870.7485 2010

-

pharmacokineti mg/kg/day =

5 and 500 48574741 The absorption of fluensulfone

- derived 14 C was rapid at both doses

. The kinetic

### Fluensulfone D427486

Page 51 of 57 Table A.2.4

. Toxicity Profile

- Fluensulfone
Guideline Study Type Doses Tested/Study Classification MRID Results

cs, single oral

rat ( [ thiazole

14 C] MCW

- 2 and [ butene

14 C] MCW

- 2 ) Acceptable/Guideline parameters for males and females were generally similar for the butene radiolabel, while for the thiazole label, male rats demonstrated a slightly higher absorption based on AUC values in whole blood

. Fluensulfone reacts with the free thiol moiety of globin (protein of hemoglobin) to form a co valent linkage to the thiazole group and displaces butene sulfinic acid. 870.7485 2011

-

toxicokinetic study

- rat ( [ thiazole

14 C] MCW

- 2 and [ butene

14 C] MCW

- 2 ) mg/kg/day =

5 and 500

Acceptable/Guideline 48574743 Residues were generally similar between males and females

. For both labels and both dose levels, the gastrointestinal tract, liver and kidney were among the tissues containing the highest radioactivity levels at C max for both sexes

. As predicted by the pharmacokinetic study, radioactivity from
t he thiazole label was slowly eliminated from red blood cells consistent with the derivatization of the hemoglobin cysteine thiol

. The ratio of residues at the C max compared to the DT 90 was near the expected 10% for plasma, but for the thiazole label (low and high doses) was >25% for numerous tissues/organs

. For the butene label (low and high doses), the ratio of residues at C max compared to DT 90 was also >25% for numerous tissues/organs except those involved with the digestive system

. The slow elimination of radioactivity with the thiazole and butene labels may reflect metabolism of [ 14 C] fluensulfone to 1

- and 2

- carbon fragments with reincorporation in natural products (e.g

. protein, fa tty acids) with long turnover
rates. 870.7600 2011 Dermal

penetration in vivo

– male rat Mg/cm 2 = 0.1 (label

dilution of commercial formulation) and 4.8 (undiluted commercial formulation) 480 EC formulation ; e quivalent to 10 g a.i./L and 480 g a.i./L, respectively. All animals exposed for 10 hours, then monitored at 24, 72 or 120 hrs. 48574949 MCW

- 2 as the MCW

- 2 480 EC formulation penetrated rat skin at both high and low dose levels at a relatively high level (63.71 and 19.16% AD at 10 hours, respective ly), which was mainly excreted in the urine. The maximum potentially absorbable % AD for the low and high dose groups is 64% at 10 hrs and 21% at 24 h, respectively. After five days, 2.2% of low dose and 0.66% of high dose radioactivity remained in the ani mals. The calculated penetration rates did not increase in a proportional fashion with dose. 870.7800 2011

- 28

- day

immunotoxicity

- mice mg/kg/day =

0, 17, 86, 204

Acceptable/Guideline 48574779 Systemic: NOAEL (mg/kg/day): 86 LOAEL (mg/kg/day): 204 based on mortality, clinical signs and decreased body

### Fluensulfone D427486

Page 52 of 57 Table A.2.4

. Toxicity Profile

- Fluensulfone
Guideline Study Type Doses Tested/Study Classification MRID Results

weight and food consumption.

Immunotoxicity: NOAEL (mg/kg/day): 204 LOAEL (mg/kg/day): not determined Special study 2011

– 3 or 7

-

day dietary study evaluating BrdU incorporation in lungs

– female mice 0 or 1200 ppm

Acceptable/nonguideline 48574767 A t 1200 ppm increased cell proliferation was observed in the lungs as determined by BrdU incorporation

. The effect was transient, observed at 3 days but not after 7 days.

Special study 2011

–

Comparative biotransformati on in human vs. mouse lung microsomes 2 or 20 μM, in vitro

incubation

Acceptable/nonguideline 48574768 Fluensulfone was extensively metabolized by mouse lung microsomes but not by human lung microsomes. Mouse Cyp2f2 appeared to be involved in the metabolism.

Special study 2009

–

Inhibition of Alanine

aminotransferas e (ALAT) in a 28

- day dog dietary study 0, 50, 200 or 900 ppm

Acceptable/nonguideline 48574775 Liver, serum and liver cytosolic fractions of untreated dogs, spiked with serum or cytosolic fractions from fluensulfone

treated dogs, did not show inhibition of ALAT activity in the untreated dogs. The decrease in ALAT activity was therefore not likely to be due to direct inhibition of the enzyme by fluensulfone/ metabolites, or inhibition of the ALAT gene or protein expression in the liver. Special study 2011

– 2

- week

dietary study in dog

– evaluation of MOA for decreased ALAT activity 0 or 500 ppm

Acceptable/nonguideline 48574776 Reduced ALAT activity was not due to decreased mRNA or protein expression, or decreased cofactor pyridoxal 5’

- phosphate.

Special study 2010

– in vitro

inhibition of ALAT activity by fluensulfone from liver microsomes of untreated dogs Up to approximately 19.1

μM, in vitro incubation

Acceptable/nonguideline 48574777 Fluensulfone did not cause a direct inhibition of ALAT activity when incubated with dog liver homogenates.

Special study 2009

–

Determination of hepatic ALAT in untreated dogs Untreated animals 48574778 An historical database for adult male and female beagle dogs was established based on data collected between 6/09 and 9/09

Special Study 2011

-

comparative in vitro dermal mg/cm 2 =

0.1 and 4.8 480 EC formulation. 48574950 The total absorption was calculated to be 92.1 1 % and 81. 26 % (low and high dose), and 62.46% and 4.65% (low and high dose)

### Fluensulfone D427486

Page 53 of 57 Table A.2.4

. Toxicity Profile

- Fluensulfone
Guideline Study Type Doses Tested/Study Classification MRID Results

absorption ( MCW

- 2 [Ring

- U

14 C] ) Acceptable/nonguideline for rat and human skin membranes, respectively

. Based on percentages absorbed, the ratio between human and rat skin membrane was 1:1.5 for the low dose level and 1:18 for the high dose level.

Special Study 2014

- 28

- Day

Dietary

– rat [BSA] mg/kg/day =

M: 0, 6.4, 30, 82, 732 F: 0, 8.6, 39, 120, 1024

Acceptable/nonguideline 49387602 NOAEL (mg/kg/day): None LOAEL (mg/kg/day): None

Aside from marginal (<25%) decreases in mean serum aspartate aminotransferase levels in both sexes and alanine aminotransferase levels in males at the high dose of 10,000 ppm, no treatment

- related effects were observed in this study up to the highest dose tested. Special Study 2014

- 28

- Day

Dietary

– rat [TSA] mg/kg/day =

M: 0, 10, 41, 113, 1194 F: 0, 12, 43, 123, 1779

Acceptable/nonguideline 49387601 NOAEL (mg/kg/day): None LOAEL (mg/kg/day): None

N o treatment

- related effects were observed in this study up to the highest dose tested. Special Study 2015

-

comparative in vitro dermal absorption mg/cm 2 =

0.09 and 4.5 480 EC formulation. 49700504 The total absorption was calculated to be 43

. 6 % and 24

. 2 % (low and high dose), and 7.1 % and 1

. 0 % (low and high dose) for rat and human skin membranes, respectively

.



### Only new or modified toxicological parameters or points of departure are discussed here. Information related to other scenarios is available in D403767, M. Doherty et al., 18 June 2014.

A.3.4 Dermal Absorption

An in vivo dermal absorption study in the rat and two in vitro dermal absorption study using rat and human skin were submitted

. All three studies used fluensulfone in an emulsifiable

concentrate (EC) formulation as the test material

. The data demonstrated an inverse relationship between dosing concentration and percent absorption

. Based on in vivo dermal absorption observed in the rat and in vitro comparative rat:human abs orption data, an estimated human dermal absorption factor (DAF) was obtained as follows (all absorption values adjusted for recovery):

(1) In the rat in vivo dermal absorption study, a dermal absorption of 58.0% (directly absorbed plus absorbable) was fou nd at 24 hrs post

- exposure using an application of 0.0953 mg/cm 2 

### ; (2) I n vitro exposure of split

- thickness rat skin under the same exposure and assessment conditions gave a dermal absorption of 43.6% (directly absorbed plus absorbable); (3) The ratio of the rat in vitro to the rat in vivo absorption is 0.75 (43.6/58.0) which is close to 1, indicating that the in vitro data is predictive of in vivo absorption;

### Fluensulfone D427486

Page 54 of 57 (4) Based on this ratio, a DAF for humans may be calculated using in vitro human dermal absorpti on (7.1%, directly absorbed plus absorbable) observed in vitro under the same exposure conditions

. The DAF for humans is therefore 7.1%/0.75= 9.5%.

A.3.5 Dermal Exposure (Short

- and Intermediate

- Term)

Study Selected: 2

- year toxicity/carcinogenicity study (rat)

.

MRID Nos: 4857476 5

Dose and Endpoint for Risk Assessment : NOAEL = 9. 6 mg/kg/day based on decreased body weight in males, and hematology changes, clinical chemistry changes and histopathological effects in the lung and esophagus of both sexes at the LOAEL of 5 7.7 mg/kg/day.

Uncertainty Factor: 100x (10x interspecies extrapolation, 10x intraspecies variability)

Comments about Study/Endpoint/Uncertainty Factor: For short

- and /or intermediate

- term residential/occupational exposure scenarios in volving dermal exposure, HED did not cho o se the 28

- day dermal toxicity study in rats conducted with the technical material

. Although that study is of the appropriate route and duration, the results using the technical material do not appear to reflect the high dermal absorption of the emulsifiable concentrate (480 EC) observed in the in vivo and in vitro dermal penetrations studies

. Given the lack of toxic response in the dermal toxicity study, HED has concluded that it is not representative of potential sy stemic exposure to fluensulfone from the 480 EC formulation, to which exposure would actually occur. Therefore, HED chose the chronic rat study discussed above, with a 9.5% dermal absorption factor to derive the point

- of

- departure . The chronic rat study was considered appropriate for short

- and intermediate

- term exposure as described above for incidental oral exposure. In addition to the rationale provided above, the 28

- day rat and 90

- day rat studies were not considered appropriate for a dermal endpoint because the primary effects observed at the LOAEL in each study were either α

- 2

- microglobulin induced kidney effects that are not relevant for human risk assessment (28

- and 90

- day rat) or portal

- of

- entry effects that would not be ex pected following dermal exposure (90

- day rat).

A.3. 6 Inhalation Exposure (Short

- and Intermediate

- Term)

Study Selected: 90

- day inhalation toxicity study in rats

.

MRID No: 48575045

Executive Summary: See Appendix A.4, Guideline 870.3465

Dose and Endpoint for Risk Assessment : NOAEL = not identified based on decreased weight gain in males, increased prothrombin time in females, decreased thymus weight in males and histopathology in the epiglottis in both sexes seen at LOAEL= 0.04 mg/L (lowest dose t ested)

.

### Fluensulfone D427486

Page 55 of 57 HEC (occupational): rat NOAEL x (daily duration adjustment) x weekly daily duration adjustment x RDDR = 0.04 mg/L x (6 hr/8 hr) x (1) x 0.143 = 0.004 3 mg/L.

HEC (residential handler): rat NOAEL x RDDR = 0.04 mg/L x 0.143 = 0.0057 mg/L.

HED (occupational): HEC x conversion factor for breathing rate in L/hr

- kg bw x human daily exposure duration in hours = 0.00429 mg/L x 11.8 L/hr

- kg bw x 8 = 0.4 1

. HED (residential handler): HEC x conversion factor for breathing rate in L/hr

- kg bw x human daily exposure duration in hours = 0.00 572 mg/L x 11.8 L/hr

- kg bw x 2 = 0.1 4 mg/kg/day.

Fluensulfone: HECs and HEDs: 90

- day Subchronic Inhalation Study in Rats ( MRID 49067003 )

Short and intermediate

term Inhalation Inhalation NOAEL = not

identified UF A = 3X UF H =10X UF L =10X Residential and

Occupational LOC for MOE = 300 Inhalation LOAEL = 0.04

mg/L based on weight loss in males, prolonged prothrombin time in females, decreased thymus weight in males, histopathological changes in the epiglottis in both sexes, and histopathological changes in the nasal cavity of males.

. Exposure Effect HECs HEDs Occupational Handler HECs and HEDs Portal of entry 0.004 3 0.4 1

Systemic 0.077 7.3

Residential HECs and HEDs Portal of entry 0.0057 0.1 4

Systemic 0.10 2.4



### Uncertainty Factor: 300x (3x interspecies extrapolation, 10x intraspecies variability, 10x extrapolation from LOAEL to NOAEL)

Comments about Study/Endpoint/Uncertainty Factors : The 90

- day inhalation toxicity study in rats was chosen because it is the only study available of the appropriate route and duration

. An additional uncertainty factor of 10x for the extrapolation from a LOAEL to a NOAEL was applied

. The interspecies uncertainty factor was reduced to 3x because of adjustment for species differences in pharmacokinetics.

### Fluensulfone D427486

Page 56 of 57 Appendix B

. Physical/Chemical Properties

Table B.1

. Physicochemical Properties of the Technical Grade Fluensulfone Parameter Value Reference Molecular weight (g/mole) 291.7 EPA/PMRA joint review of fluensulfone technical

grade active ingredient

. Monograph Volume 3, Parts B1 and B2

. B

. Kitchens

. December 2013. Melting point/range (°C) 34.8 ± 0.5 pH 5.11 (1% solution at 21°C) Density (g/cm 3 ) 1.876 Water solubility ( g /L at 20° C) 0.5453 Organic s olvent solubility (g/L at 20° C) Acetone 350.49 Dichloromethane 306.14 Ethyl acetate 350.76

n

- Heptane 19.01 Methanol 359.29

n

- Octanol 90.42 Xylene 356.18
Vapor pressure at 25 °C (Pa) 3.0 x 10

- 2 Dissociation constant (pK a ) No acidic or basic functional
groups Octanol/water partition coefficient Log(K OW ) 2.2

### Fluensulfone D427486

Page 57 of 57 Appendix C

. Review of Human Research

This risk assessment relies in part on data from studies in which adult human subjects were intentionally exposed to a pesticide or other chemical

. These data, which include studies from PHED 1.1 and the AHETF database are (1) subject to ethics review pursuant to 40 CFR 26, (2) have received that review, and (3) are compliant with applicable ethics requirements

. For certain studies, the ethics review may have included review b y the Human Studies Review Board

. Descriptions of data sources, as well as guidance on their use, can be found at the Agency website 4



### .

4 http://www.epa.gov/pesticides/science/handler

- exposure

- data.html and http://www.epa.gov/pesticides/science/post

- app

- exposure

- data.html